6-(5-membered heteroaryl)isoquinolin-3-yl carboxamides and preparation and use thereof

ABSTRACT

Isoquinoline compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an isoquinoline compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer&#39;s disease, lung disease, inflammation, auto-immune diseases and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as neurological conditions/disorders/diseases linked to overexpression of DYRK1A.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.62/574,568, filed Oct. 19, 2017, and 62/578,691, filed Oct. 30, 2017,which are incorporated herein by reference in their entirety.

BACKGROUND Technical Field

This disclosure relates to inhibitors of one or more proteins in the Wntpathway, including inhibitors of one or more Wnt proteins, andcompositions comprising the same. More particularly, it concerns the useof an isoquinoline compound or salts or analogs thereof, in thetreatment of disorders characterized by the activation of Wnt pathwaysignaling (e.g., cancer, abnormal cellular proliferation, angiogenesis,Alzheimer's disease, lung disease, inflammation, auto-immune diseasesfibrotic disorders, cartilage (chondral) defects, and osteoarthritis),the modulation of cellular events mediated by Wnt pathway signaling, aswell as genetic diseases and neurological conditions/disorders/diseasesdue to mutations or dysregulation of the Wnt pathway and/or of one ormore of Wnt signaling components. Also provided are methods for treatingWnt-related disease states, as well as neurologicalconditions/disorders/diseases linked to overexpression of DYRK1A.

Background

The Wnt growth factor family includes more than 10 genes identified inthe mouse and at least 19 genes identified in the human. Members of theWnt family of signaling molecules mediate many short- and long-rangepatterning processes during invertebrate and vertebrate development. TheWnt signaling pathway is known for its role in the inductiveinteractions that regulate growth and differentiation, and it also playsroles in the homeostatic maintenance of post-embryonic tissue integrity.Wnt stabilizes cytoplasmic β-catenin, which stimulates the expression ofgenes including c-myc, c jun, fra-1, and cyclin Dl. In addition,misregulation of Wnt signaling can cause developmental defects and isimplicated in the genesis of several human cancers. The Wnt pathway hasalso been implicated in the maintenance of stem or progenitor cells in agrowing list of adult tissues including skin, blood, gut, prostate,muscle, and the nervous system.

Dual specificity tyrosine-phosphorylation-regulated kinase 1A is anenzyme that in humans is encoded by the DYRK1A gene. DYRK1A is a memberof the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK)family. DYRK1A contains a nuclear targeting signal sequence, a proteinkinase domain, a leucine zipper motif, and a highly conservative13-consecutive-histidine repeat. It catalyzes its autophosphorylation onserine/threonine and tyrosine residues. It may play a significant rolein a signaling pathway regulating cell proliferation and may be involvedin brain development. DYRK1A is localized in the Down syndrome criticalregion of chromosome 21, and is considered to be a candidate gene forlearning defects associated with Down syndrome. DYRK1A is also expressedin adult brain neurons, indicating that DYRK1A may play a role in themature central nervous system. Thus, several lines of evidence point tosome synaptic functions of DYRK1A. For instance, it has been found thatDYRK1A phosphorylates and modulates the interaction of severalcomponents of the endocytic protein complex machinery (Dynamin 1,Amphiphysin, and Synaptojanin), suggesting a role in synaptic vesiclerecycling. In addition, a polymorphism (SNP) in DYRK1A was found to beassociated with HIV-1 replication in monocyte-derived macrophages, aswell as with progression to AIDS in two independent cohorts ofHIV-1-infected individuals.

SUMMARY

The present disclosure provides methods and reagents, involvingcontacting a cell with an agent, such as an isoquinoline compound, in asufficient amount to antagonize a Wnt activity, e.g., to reverse orcontrol an aberrant growth state or correct a genetic disorder due tomutations in Wnt signaling components.

The present disclosure also provides methods and reagents, involvingcontacting a cell with an agent, such as an isoquinoline compound, in asufficient amount to antagonize DYRK1A activity, e.g., i) to normalizeprenatal and early postnatal brain development; ii) to improve cognitivefunction in youth and adulthood; and/or iii) to attenuateAlzheimer's-type neurodegeneration.

Some embodiments disclosed herein include Wnt and/or DYRK1A inhibitorscontaining an isoquinoline core. Other embodiments disclosed hereininclude pharmaceutical compositions and methods of treatment using thesecompounds.

One embodiment disclosed herein includes a compound having the structureof Formula I:

as well as prodrugs and pharmaceutically acceptable salts thereof.

In some embodiments of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R²⁶;

with the proviso that R³ is not

R⁶ is selected from the group consisting of —CH₂phenyl substituted with1-5 R⁴¹, —CH═CHphenyl optionally substituted with halide, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R²⁷,-carbocyclyl substituted with 1-5 R²⁸, and

wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; wherein n is 1-4, m is 0-2 andeach Z is independently selected from the group consisting of CR³² andN;

each R²⁶ is independently unsubstituted —(C₁₋₅ alkyl);

each R²⁷ is independently selected from the group consisting of halideand —N(R⁴³)(R⁴⁴) with the proviso that if one or more R²⁷ is halide, atleast one R²⁷ is —N(R⁴³)(R⁴⁴);

each R²⁸ is independently —N(R³³)(R³⁴);

each R³² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

R³³ is attached to the nitrogen and selected from the group consistingof H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

R³⁴ is attached to the nitrogen and is selected from the groupconsisting of unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁹, —(C₁₋₄alkylene)OR³⁵; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

each R³⁵ is independently selected from the group consisting of H andunsubstituted —(C₁₋₅ alkyl);

each R³⁸ is independently selected from the group consisting of halideand unsubstituted —(C₁₋₅ alkyl);

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁰;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴¹ is independently selected from the group consisting of halideand —OMe;

each R⁴³ is attached to the nitrogen and selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl);

each R⁴⁴ is attached to the nitrogen and is selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with1-12 R³⁹, —(C₁₋₄ alkylene)OR³⁵; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each p is independently 0 or 1; and

wherein one or more H are optionally replaced by D.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is selected from the group consisting of:

wherein each of R⁷-R²⁵ is, independently, a substituent or a single bondconnecting R³ to the isoquinoline ring; wherein only one of R⁷-R¹⁰ (whenpresent) is a bond, only one of R¹¹-R¹⁴ (when present) is a bond, onlyone of R¹⁵-R⁷ (when present) is a bond, only one of R¹⁸-R²⁰ (whenpresent) is a bond, only one of R²¹-R²³ (when present) is a bond, andonly one of R²⁴-R²⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,or R¹⁸ can serve as the point of attachment of R³ to the isoquinolinering; likewise, any one of the carbon atoms attached to R⁸, R⁹, R¹⁰,R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, and R²⁵, canserve as the point of attachment of R³ to the isoquinoline ring; sothat:

when the nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is selected from the group consisting of —CH₂phenyl substituted with1-5 R⁴¹, —CH═CHphenyl optionally substituted with halide, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R²⁷,-carbocyclyl substituted with 1-5 R²⁸, and

wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; wherein n is 1-4, m is 0-2 andeach Z is independently selected from the group consisting of CR³² andN;

R⁷ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, and unsubstituted —(C₁₋₅ alkyl);

R¹¹ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R¹², R¹³, and R¹⁴ are independently selected from the group consistingof a single bond, H, and unsubstituted —(C₁₋₅ alkyl);

R¹⁵ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R¹⁶ and R¹⁷ are independently selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl);

R¹⁸ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R¹⁹ and R²⁰ are independently selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl);

R²¹, R²², and R²³ are independently selected from the group consistingof a single bond, H, and unsubstituted —(C₁₋₅ alkyl);

R²⁴ and R²⁵ are independently selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl);

each R²⁷ is independently selected from the group consisting of halide,and —N(R⁴³)(R⁴⁴) with the proviso that if one or more R²⁷ is halide, atleast one R²⁷ is —N(R⁴³)(R⁴⁴);

each R²⁸ is independently —N(R³³)(R³⁴);

each R³² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

R³³ is attached to the nitrogen and selected from the group consistingof H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

R³⁴ is attached to the nitrogen and is selected from the groupconsisting of unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁹, —(C₁₋₄alkylene)OR³⁵; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

each R³⁵ is independently selected from the group consisting of H andunsubstituted —(C₁₋₅ alkyl);

each R³⁸ is independently selected from the group consisting of halideand unsubstituted —(C₁₋₅ alkyl);

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁰;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴¹ is independently selected from the group consisting of halideand —OMe;

each R⁴³ is attached to the nitrogen and selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl);

each R⁴⁴ is attached to the nitrogen and is selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-10 R³⁸, —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with1-12 R³⁹, —(C₁₋₄ alkylene)OR³⁵; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each X is O or S;

each p is independently 0 or 1; and

wherein one or more H are optionally replaced by D.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R²⁶;

with the proviso that R³ is not

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R²⁷,-carbocyclyl optionally substituted with 1-5 R²⁸, and —N(R³⁰)(R³¹);wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

each R²⁶ is independently unsubstituted —(C₁₋₅ alkyl);

each R²⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₁₋₉ haloalkyl), —OR³⁵, and—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-5 R³⁶;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

each R²⁸ is independently selected from the group consisting of—N(R³³)₂, —(C₁₋₄ alkylene)OR³⁵, —C(═O)(R³⁷), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R³⁶; whereineach —(C₁₋₄ alkylene) is independently, optionally substituted with oneor more substituents as defined anywhere herein;

R³⁰ is attached to the nitrogen and is selected from the groupconsisting of H and unsubstituted —(C₁₋₅ alkyl);

R³¹ is attached to the nitrogen and is heterocyclyl optionallysubstituted with 1-5 R³⁸;

R³³ is attached to the nitrogen and selected from the group consistingof H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl), andunsubstituted —(C₂₋₅ alkynyl);

each R³⁵ is independently selected from the group consisting of H andunsubstituted —(C₁₋₅ alkyl);

each R³⁶ is selected from the group consisting of unsubstituted —(C₁₋₅alkyl) and unsubstituted —(C₁₋₅ haloalkyl);

R³⁷ is -heterocyclyl optionally substituted with one or more halides orone or more unsubstituted —(C₁₋₅ alkyl);

each R³⁸ is independently selected from the group consisting of halideand unsubstituted —(C₁₋₅ alkyl);

each p is independently 0 or 1; and

wherein one or more H are optionally replaced by D.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is selected from the group consisting of:

wherein each of R⁷-R²⁵ is, independently, a substituent or a single bondconnecting R³ to the isoquinoline ring; wherein only one of R⁷-R¹⁰ (whenpresent) is a bond, only one of R¹¹-R⁴ (when present) is a bond, onlyone of R¹⁵-R¹⁷ (when present) is a bond, only one of R⁸-R²⁰ (whenpresent) is a bond, only one of R²¹-R²³ (when present) is a bond, andonly one of R²⁴-R²⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,or R¹⁸ can serve as the point of attachment of R³ to the isoquinolinering; likewise, any one of the carbon atoms attached to R⁸, R⁹, R¹⁰,R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, and R²⁵, canserve as the point of attachment of R³ to the isoquinoline ring; sothat: when the nitrogen atom to which R⁷ is attached serves as the pointof attachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁴ is a single bondconnecting R³ to the isoquinoline ring; when the nitrogen atom to whichR¹⁵ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁵ is a single bond connecting R³ to theisoquinoline ring;

when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁷ is a single bondconnecting R³ to the isoquinoline ring; when the nitrogen atom to whichR¹⁸ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁸ is a single bond connecting R³ to theisoquinoline ring;

when the carbon atom to which R¹⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R^(2′) is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R^(2′) is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R²⁷,-carbocyclyl optionally substituted with 1-5 R²⁸, and —N(R³⁰)(R³¹);wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

R⁷ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, and unsubstituted —(C₁₋₅ alkyl);

R¹¹ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R¹², R¹³, and R¹⁴ are independently selected from the group consistingof a single bond, H, and unsubstituted —(C₁₋₅ alkyl);

R¹⁵ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R¹⁶ and R¹⁷ are independently selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl);

R¹⁸ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R¹⁹ and R²⁰ are independently selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl);

R²¹, R²², and R²³ are independently selected from the group consistingof a single bond, H, and unsubstituted —(C₁₋₅ alkyl);

R²⁴ and R²⁵ are independently selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl);

each R²⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₁₋₉ haloalkyl), —OR³⁵, and—(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-5 R³⁶;wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein;

each R²⁸ is independently selected from the group consisting of—N(R³³)₂, —(C₁₋₄ alkylene)OR³⁵, —C(═O)(R³⁷), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R³⁶; whereineach —(C₁₋₄ alkylene) is independently, optionally substituted with oneor more substituents as defined anywhere herein;

R³⁰ is attached to the nitrogen and is selected from the groupconsisting of H and unsubstituted —(C₁₋₅ alkyl);

R³¹ is attached to the nitrogen and is heterocyclyl optionallysubstituted with 1-5 R³⁸;

R³³ is attached to the nitrogen and selected from the group consistingof H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl), andunsubstituted —(C₂₋₅ alkynyl); each R³⁵ is independently selected fromthe group consisting of H and unsubstituted —(C₁₋₅ alkyl);

each R³⁶ is selected from the group consisting of unsubstituted —(C₁₋₅alkyl) and unsubstituted —(C₁₋₅ haloalkyl);

R³⁷ is -heterocyclyl optionally substituted with one or more halides orone or more unsubstituted —(C₁₋₅ alkyl);

each R³⁸ is independently selected from the group consisting of halideand unsubstituted —(C₁₋₅ alkyl);

each X is O or S; and

each p is independently 0 or 1; and

wherein one or more H are optionally replaced by D.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R²⁶;

R⁶ is a selected from the group consisting of -phenyl substituted with1-5 R⁴² and 6-membered heteroaryl optionally substituted with 1-6 R²⁹;

each R²⁶ is independently unsubstituted —(C₁₋₅ alkyl);

each R²⁹ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl) and heterocyclyl optionally substituted with1-5 R³⁶;

each R³⁶ is independently unsubstituted —(C₁₋₅ alkyl);

each R⁴² is independently selected from the group consisting of halide,—OMe, and unsubstituted —(C₁₋₅ alkyl); and

wherein one or more H are optionally replaced by D.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is selected from the group consisting of:

wherein each of R⁷-R¹⁰ and R²¹-R²⁵ is, independently, a substituent or asingle bond connecting R³ to the isoquinoline ring; wherein only one ofR⁷-R¹⁰ (when present) is a bond, only one of R²¹-R²³ (when present) is abond, and only one of R²⁴-R²⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷ can serve asthe point of attachment of R³ to the isoquinoline ring; likewise, anyone of the carbon atoms attached to R⁸, R⁹, R¹⁰, R²¹, R²², R²³, R²⁴, orR²⁵ can serve as the point of attachment of R³ to the isoquinoline ring;so that:

when the nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is a selected from the group consisting of -phenyl substituted with1-5 R⁴² and 6-membered heteroaryl optionally substituted with 1-6 R²⁹;

R⁷ is selected from the group consisting of H, and unsubstituted —(C₁₋₅alkyl);

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, unsubstituted —(C₁₋₅ alkyl);

R²¹, R²², and R²³ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₅ alkyl);

R²⁴ and R²⁵ are independently selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₅ alkyl);

each R²⁹ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl) and heterocyclyl optionally substituted with1-5 R³⁶;

each R³⁶ is independently unsubstituted —(C₁₋₅ alkyl);

each R⁴² is independently selected from the group consisting of halide,—OMe, and unsubstituted —(C₁₋₅ alkyl);

each X is O or S: and

wherein one or more H are optionally replaced by D.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R²⁶;

R⁶ is a selected from the group consisting of -phenyl substituted with1-5 R⁴² and 6-membered heteroaryl optionally substituted with 1-6 R²⁹;

each R²⁶ is independently unsubstituted —(C₁₋₅ alkyl);

each R²⁹ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), heterocyclyl optionally substituted with1-5 R³⁶, and N-oxide;

each R³⁶ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl) and N-oxide;

each R⁴² is independently selected from the group consisting of halide,—OMe, and unsubstituted —(C₁₋₅ alkyl); and

wherein one or more H are optionally replaced by D.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H and halide;

R³ is selected from the group consisting of:

wherein each of R⁷-R¹⁰ and R²¹-R²⁵ is, independently, a substituent or asingle bond connecting R³ to the isoquinoline ring; wherein only one ofR⁷-R¹⁰ (when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is abond, only one of R²¹-R²³ (when present) is a bond, and only one ofR²⁴-R²⁵ (when present) is a bond; for purposes of clarification, any oneof the nitrogen atoms attached to R⁷ can serve as the point ofattachment of R³ to the isoquinoline ring; likewise, any one of thecarbon atoms attached to R⁸, R⁹, R¹⁰, R¹⁵, R¹⁶, R¹⁷, R²¹, R²², R²³, R²⁴,or R²⁵ can serve as the point of attachment of R³ to the isoquinolinering; so that:

when the nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁰ is a single bondconnecting R³ to the isoquinoline ring; when the nitrogen atom to whichR¹⁵ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁵ is a single bond connecting R³ to theisoquinoline ring;

when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is a selected from the group consisting of -phenyl substituted with1-5 R⁴² and 6-membered heteroaryl optionally substituted with 1-6 R²⁹;

R⁷ is selected from the group consisting of H, and unsubstituted —(C₁₋₅alkyl);

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, unsubstituted —(C₁₋₅ alkyl);

R¹⁵ is selected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl);

R¹⁶ and R¹⁷ are independently selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl);

R²¹, R²², and R²³ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₅ alkyl);

R²⁴ and R²⁵ are independently selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₅ alkyl);

each R²⁹ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), heterocyclyl optionally substituted with1-5 R³⁶, and N-oxide;

each R³⁶ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl) and N-oxide;

each R⁴² is independently selected from the group consisting of halide,—OMe, and unsubstituted —(C₁₋₅ alkyl);

each X is O or S; and

wherein one or more H are optionally replaced by D.

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of Formula (I). Some embodiments includepharmaceutically acceptable salts of a compound of Formula (I).

Some embodiments include pro-drugs of a compound of Formula (I).

Some embodiments of the present disclosure include pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Other embodiments disclosed herein include methods of inhibiting one ormore members of the Wnt pathway, including one or more Wnt proteins byadministering to a patient affected by a disorder or disease in whichaberrant Wnt signaling is implicated, such as cancer and other diseasesassociated with abnormal angiogenesis, cellular proliferation, cellcycling and mutations in Wnt signaling components, a compound accordingto Formula (I). Accordingly, the compounds and compositions providedherein can be used to treat cancer, to reduce or inhibit angiogenesis,to reduce or inhibit cellular proliferation and correct a geneticdisorder due to mutations in Wnt signaling components.

Other embodiments disclosed herein include methods of inhibiting DYRK1Aby administering to a patient affected by a disorder or disease in whichDYRK1A overexpression is implicated, such as Alzheimer's Disease,Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementiawith Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease,Pick's Disease, and additional diseases with pronouncedneurodegeneration such as Autism, Dementia, Epilepsy, Huntington'sDisease, Multiple Sclerosis; diseases and disorders associated withacquired brain injury such as Chronic Traumatic Encephalopathy,Traumatic Brain Injury, Tumor and Stroke.

Non-limiting examples of diseases which can be treated with thecompounds and compositions provided herein include a variety of cancers,diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis,ankylosing spondylitis, psoriasis, scleroderma, mycotic and viralinfections, osteochondrodysplasia, Alzheimer's disease, lung disease,bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articularcartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Some embodiments of the present disclosure include methods to preparecompounds of Formula (I).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosure, as claimed.

DETAILED DESCRIPTION

Provided herein are compositions and methods for inhibiting one or moremembers of the Wnt pathway, including one or more Wnt proteins. OtherWnt inhibitors and methods for using the same are disclosed in U.S.application Ser. Nos. 13/614,296; 14/019,229; and Ser. No. 14/664,517,all of which are incorporated by reference in their entirety herein.

Provided herein are compositions and methods for inhibiting DYRK1A.Other DYRK1A inhibitors and methods for using the same are disclosed inU.S. application Ser. No. 14/664,517, which is incorporated by referencein its entirety herein.

Some embodiments provided herein relate to a method for treating adisease including, but not limited to, neurological diseases ordisorders, cancers, chronic inflammation, diabetic retinopathy,pulmonary fibrosis, rheumatoid arthritis, sepsis, ankylosingspondylitis, psoriasis, scleroderma, mycotic and viral infections, boneand cartilage diseases, lung disease, osteoarthritis, articularcartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), polyposis coli, bone density andvascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG),familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia, Müllerian-duct regression andvirilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

In some embodiments, non-limiting examples of bone and cartilagediseases which can be treated with the compounds and compositionsprovided herein include bone spur (osteophytes), craniosynostosis,fibrodysplasia ossificans progressive, fibrous dysplasia, giant celltumor of bone, hip labral tear, meniscal tears, osteoarthritis,articular cartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), osteochondritis dissecans,osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis,and Salter-Harris fractures.

In some embodiments, non-limiting examples of a neurological disease ordisorder associated with tau protein, amyloid or alpha-synucleinpathology which can be treated with the compounds and compositionsprovided herein include, but are not limited to, Alzheimer's Disease,Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementiawith Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's Disease,Pick's Disease, and additional diseases with pronouncedneurodegeneration such as Autism, Dementia, Epilepsy, Huntington'sDisease, Multiple Sclerosis; diseases and disorders associated withacquired brain injury such as Chronic Traumatic Encephalopathy,Traumatic Brain Injury, Tumor, and Stroke.

In some embodiments, non-limiting examples of diseases in which chronicinflammation is involved which can be treated with the compounds andcompositions provided herein include eye disorders, joint pain,arthritis (rheumatoid, osteo, psoriatic gout), cancers (colon, breast,lung, pancreas, and others), gastrointestinal disorders (ulcerativecolitis and inflammatory bowel diseases), pulmonary disorders (chronicobstructive pulmonary disorder and asthma), allergies, skin disorders(atopic dermatitis and psoriasis), diabetes, pancreatitis, tendonitis,hepatitis, heart disease, myocarditis, stroke, lupus, and neurologicaldisorders such as multiple sclerosis, Parkinson's and dementia includingAlzheimer's disease.

In some embodiments, non-limiting examples of cancers which can betreated with the compounds and compositions provided herein includecolon, ovarian, pancreatic, breast, liver, prostate, and hematologiccancers.

In some embodiments, pharmaceutical compositions are provided that areeffective for treatment of a disease of an animal, e.g., a mammal,caused by either the pathological activation or mutations of the Wntpathway or DYRK1A overexpression. The composition includes apharmaceutically acceptable carrier and a compound as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, “alkyl” means a branched, or straight chain chemicalgroup containing only carbon and hydrogen, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can eitherbe unsubstituted or substituted with one or more substituents. In someembodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenyl” means a straight or branched chain chemicalgroup containing only carbon and hydrogen and containing at least onecarbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In variousembodiments, alkenyl groups can either be unsubstituted or substitutedwith one or more substituents. Typically, alkenyl groups will comprise 2to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbonatoms, or 2 carbon atoms).

As used herein, “alkynyl” means a straight or branched chain chemicalgroup containing only carbon and hydrogen and containing at least onecarbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl,2-butynyl, and the like. In various embodiments, alkynyl groups caneither be unsubstituted or substituted with one or more substituents.Typically, alkynyl groups will comprise 2 to 9 carbon atoms (forexample, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkylene” means a bivalent branched, or straight chainchemical group containing only carbon and hydrogen, such as methylene,ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene,sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentyleneand neo-pentylene. Alkylene groups can either be unsubstituted orsubstituted with one or more substituents. In some embodiments, alkylenegroups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenylene” means a bivalent branched, or straightchain chemical group containing only carbon and hydrogen and containingat least one carbon-carbon double bond, such as ethenylene,1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene,2-butenylene, and the like. In various embodiments, alkenylene groupscan either be unsubstituted or substituted with one or moresubstituents. Typically, alkenylene groups will comprise 2 to 9 carbonatoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2carbon atoms).

As used herein, “alkynylene” means a bivalent branched, or straightchain chemical group containing only carbon and hydrogen and containingat least one carbon-carbon triple bond, such as ethynylene,1-propynylene, 1-butynylene, 2-butynylene, and the like. In variousembodiments, alkynylene groups can either be unsubstituted orsubstituted with one or more substituents. Typically, alkynylene groupswill comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkoxy” means an alkyl-O— group in which the alkylgroup is as described herein. Exemplary alkoxy groups include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy,hexoxy and heptoxy, and also the linear or branched positional isomersthereof.

As used herein, “haloalkoxy” means a haloalkyl-O— group in which thehaloalkyl group is as described herein. Exemplary haloalkoxy groupsinclude fluoromethoxy, difluoromethoxy, trifluoromethoxy, and also thelinear or branched positional isomers thereof.

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that none of the rings in the ring system arearomatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents. In some embodiments, carbocyclyl groupsinclude 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group withonly carbon atoms present in the ring backbone having 5 to 14 ringatoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14pi electrons shared in a cyclic array; wherein at least one ring in thesystem is aromatic. Aryl groups can either be unsubstituted orsubstituted with one or more substituents. Examples of aryl includephenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, andothers. In some embodiments, the aryl is phenyl.

As used herein, “arylalkylene” means an aryl-alkylene-group in which thearyl and alkylene moieties are as previously described. In someembodiments, arylalkylene groups contain a C₁₋₄alkylene moiety.Exemplary arylalkylene groups include benzyl and 2-phenethyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- orpolycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclicarray; wherein at least one ring in the system is aromatic, and at leastone ring in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S. Heteroaryl groups caneither be unsubstituted or substituted with one or more substituents.Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl,oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl,isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl,benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl,pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In someembodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl,pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, andpyrimidinyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo,fluoro, or iodo atom radical. In some embodiments, a halo is a chloro,bromo or fluoro. For example, a halide can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched, alkyl, alkenyl or alkynyl substituted with one ormore chloro, bromo, fluoro, and/or iodo atom(s). In some embodiments, ahaloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atomshave been substituted by fluoro. In some embodiments, haloalkyls are of1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or1 carbon in length). The term “haloalkylene” means a diradical variantof haloalkyl, and such diradicals may act as spacers between radicals,other atoms, or between a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring systemcomprising at least one heteroatom in the ring system backbone.Heterocyclyls may include multiple fused rings. Heterocyclyls may besubstituted or unsubstituted with one or more substituents. In someembodiments, heterocycles have 3-11 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one to three of O, Nor S, and wherein when the heterocycle is five membered, it can have oneor two heteroatoms selected from O, N, or S. Examples of heterocyclylinclude azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl,thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.In some embodiments, the heterocyclyl is selected from azetidinyl,morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

As used herein, “monocyclic heterocyclyl” means a single nonaromaticcyclic ring comprising at least one heteroatom in the ring systembackbone. Heterocyclyls may be substituted or unsubstituted with one ormore substituents. In some embodiments, heterocycles have 3-7 members.In six membered monocyclic heterocycles, the heteroatom(s) are selectedfrom one to three of O, N or S, and wherein when the heterocycle is fivemembered, it can have one or two heteroatoms selected from O, N, or S.Examples of heterocyclyls include azirinyl, aziridinyl, azetidinyl,oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl,pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl,thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl,thiomorpholinyl, and others.

As used herein, “bicyclic heterocyclyl” means a nonaromatic bicyclicring system comprising at least one heteroatom in the ring systembackbone. Bicyclic heterocyclyls may be substituted or unsubstitutedwith one or more substituents. In some embodiments, bicyclicheterocycles have 4-11 members with the heteroatom(s) being selectedfrom one to five of O, N or S. Examples of bicyclic heterocyclylsinclude 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane,2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane,5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane,octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane,7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane,7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and the like.

As used herein, “spirocyclic heterocyclyl” means a nonaromatic bicyclicring system comprising at least one heteroatom in the ring systembackbone and with the rings connected through just one atom. Spirocyclicheterocyclyls may be substituted or unsubstituted with one or moresubstituents. In some embodiments, spirocyclic heterocycles have 5-11members with the heteroatom(s) being selected from one to five of O, Nor S. Examples of spirocyclic heterocyclyls include2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane,2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane,6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane,2,5-diazaspiro[3.6]decane, and the like.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more non-hydrogen atoms of the molecule. It will beunderstood that “substitution” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. Substituents can include, for example,—(C₁₋₉ alkyl) optionally substituted with one or more of hydroxyl, —NH₂,—NH(C₁₋₃ alkyl), and —N(C₁₋₃ alkyl)₂; —(C₁₋₉ haloalkyl); a halide; ahydroxyl; a carbonyl [such as —C(O)OR, and —C(O)R]; a thiocarbonyl [suchas —C(S)OR, —C(O)SR, and —C(S)R]; —(C₁₋₉ alkoxy) optionally substitutedwith one or more of halide, hydroxyl, —NH₂, —NH(C₁₋₃ alkyl), and —N(C₁₋₃alkyl)₂; —OPO(OH)₂; a phosphonate [such as —PO(OH)₂ and —PO(OR′)₂];—OPO(OR′)R″; —NRR′; —C(O)NRR′; —C(NR)NR′R″; —C(NR′)R″; a cyano; a nitro;an azido; —SH; —S—R; —OSO₂(OR); a sulfonate [such as —SO₂(OH) and—SO₂(OR)]; —SO₂NR′R″; and —SO₂R; in which each occurrence of R, R′ andR″ are independently selected from H; —(C₁₋₉ alkyl); C₆₋₁₀ aryloptionally substituted with from 1-3R′″; 5-10 membered heteroaryl havingfrom 1-4 heteroatoms independently selected from N, O, and S andoptionally substituted with from 1-3 R′″; C₃₋₇ carbocyclyl optionallysubstituted with from 1-3 R′″; and 3-8 membered heterocyclyl having from1-4 heteroatoms independently selected from N, O, and S and optionallysubstituted with from 1-3 R′″; wherein each R′″ is independentlyselected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), a halide (e.g., F), ahydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxyl), —NRR′, —C(O)NRR′, and acyano, in which each occurrence of R and R′ is independently selectedfrom H and —(C₁₋₆ alkyl). In some embodiments, the substituent isselected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), a halide (e.g., F), ahydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxyl), —NRR′, —C(O)NRR′, and acyano, in which each occurrence of R and R′ is independently selectedfrom H and —(C₁₋₆ alkyl).

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring”, it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions. In someembodiments, such rings have from 3-7 members, for example, 5 or 6members.

The skilled artisan will recognize that some chemical structuresdescribed herein may be represented on paper by one or more otherresonance forms; or may exist in one or more other tautomeric forms,even when kinetically, the artisan recognizes that such tautomeric formsrepresent only a very small portion of a sample of such compound(s).Such compounds are clearly contemplated within the scope of thisdisclosure, though such resonance forms or tautomers are not explicitlyrepresented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g., mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The present disclosure includes all pharmaceutically acceptableisotopically labeled compounds of Formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature. Examples of isotopes suitable for inclusion inthe compounds of the disclosure include, but are not limited to,isotopes of hydrogen, such as ²H (deuterium) and ³H (tritium), carbon,such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as³⁵S.

The term “administration” or “administering” refers to a method ofproviding a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian, where the method is, e.g., orally, subcutaneously,intravenously, intralymphatic, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic device. Themethod of administration can vary depending on various factors, e.g.,the components of the pharmaceutical composition, the site of thedisease, the disease involved, and the severity of the disease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification or characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, monkeys, dogs, cats, mice,rats, cows, sheep, pigs, goats, and non-human primates, but alsoincludes many other species.

The term “pharmaceutically acceptable carrier”, “pharmaceuticallyacceptable diluent” or “pharmaceutically acceptable excipient” includesany and all solvents, co-solvents, complexing agents, dispersion media,coatings, isotonic and absorption delaying agents and the like which arenot biologically or otherwise undesirable. The use of such media andagents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible withthe active ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions. In addition, various adjuvants such as arecommonly used in the art may be included. These and other such compoundsare described in the literature, e.g., in the Merck Index, Merck &Company, Rahway, N.J. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., inBrunton et al. (Eds.) (2017); Goodman and Gilman's: The PharmacologicalBasis of Therapeutics, 13th Ed., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and, which are not biologically or otherwise undesirable. In manycases, the compounds provided herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Many such salts are known in the art, forexample, as described in WO 87/05297. Pharmaceutically acceptable acidaddition salts can be formed with inorganic acids and organic acids.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium, and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine.

“Patient” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate, or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate. In some embodiments, the patient is a human.

A “therapeutically effective amount” of a compound as provided herein isone which is sufficient to achieve the desired physiological effect andmay vary according to the nature and severity of the disease condition,and the potency of the compound. “Therapeutically effective amount” isalso intended to include one or more of the compounds of Formula I incombination with one or more other agents that are effective to treatthe diseases and/or conditions described herein. The combination ofcompounds can be a synergistic combination. Synergy, as described, forexample, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22,27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. It will be appreciated that different concentrations may beemployed for prophylaxis than for treatment of an active disease. Thisamount can further depend upon the patient's height, weight, sex, ageand medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease.

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from a diseasethus causing a therapeutically beneficial effect, such as amelioratingexisting symptoms, ameliorating the underlying metabolic causes ofsymptoms, postponing or preventing the further development of adisorder, and/or reducing the severity of symptoms that will or areexpected to develop.

“Drug-eluting” and/or controlled release as used herein refers to anyand all mechanisms, e.g., diffusion, migration, permeation, and/ordesorption by which the drug(s) incorporated in the drug-elutingmaterial pass therefrom over time into the surrounding body tissue.

“Drug-eluting material” and/or controlled release material as usedherein refers to any natural, synthetic or semi-synthetic materialcapable of acquiring and retaining a desired shape or configuration andinto which one or more drugs can be incorporated and from whichincorporated drug(s) are capable of eluting over time.

“Elutable drug” as used herein refers to any drug or combination ofdrugs having the ability to pass over time from the drug-elutingmaterial in which it is incorporated into the surrounding areas of thebody.

Compounds

The compounds and compositions described herein can be used asanti-proliferative agents, e.g., anti-cancer and anti-angiogenesisagents, and/or as inhibitors of the Wnt signaling pathway, e.g., fortreating diseases or disorders associated with aberrant Wnt signaling.In addition, the compounds can be used as inhibitors of one or morekinases, kinase receptors, or kinase complexes. Such compounds andcompositions are also useful for controlling cellular proliferation,differentiation, and/or apoptosis.

The compounds and compositions described herein can be used to inhibitDYRK1A for treating a disorder or disease in which DYRK1A overexpressionis implicated, such as Alzheimer's Disease, Amyotrophic LateralSclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17(FTDP-17), Lewy body dementia, Parkinson's Disease, Pick's Disease, andadditional diseases with pronounced neurodegeneration such as Autism,Dementia, Epilepsy, Huntington's Disease, Multiple Sclerosis; diseasesand disorders associated with acquired brain injury such as ChronicTraumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

Some embodiments of the present disclosure include compounds of FormulaI:

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H and halide (e.g., F, Cl, Br, I);

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H and F.

In some embodiments, R¹, R², R⁴, and R⁵ are all H.

In some embodiments, R¹ is F, and R², R⁴, and R⁵ are all H.

In some embodiments, R² is F, and R¹, R⁴, and R⁵ are all H.

In some embodiments, R⁴ is F, and R¹, R², and R⁵ are all H.

In some embodiments, R⁵ is F, and R¹, R², and R⁴ are all H.

In some embodiments, R³ is a 5-membered heteroaryl ring optionallysubstituted as defined anywhere herein.

In some embodiments, R³ is 5-membered heteroaryl ring optionallysubstituted with 1-4 (e.g., 1-3, 1-2, 1) R²⁶;

In some embodiments, there is the proviso that R³ is not

In some embodiments, R³ is selected from the group consisting of:furanyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R²⁶,thiophenyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R²⁶,pyrrolyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R²⁶,

wherein each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).

In some embodiments, R³ is selected from the group consisting of:

wherein each of R⁷-R²⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹⁰ (when present) is a bond, only one of R¹¹-R¹⁴(when present) is a bond, only one of R¹⁵-R⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, and only one of R²⁴-R²⁵ (when present) is a bond;for purposes of clarification, any one of the nitrogen atoms attached toR⁷, R¹¹, R¹⁵, or R¹⁸ can serve as the point of attachment of R³ to theisoquinoline ring; likewise, any one of the carbon atoms attached to R⁸,R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, and R²⁵,can serve as the point of attachment of R³ to the isoquinoline ring.

In some embodiments, R³ is selected from the group consisting of:

wherein each of R⁷-R¹⁰ and R²¹-R²⁵ is, independently, a substituent asdefined anywhere herein or a single bond connecting R³ to theisoquinoline ring; wherein only one of R⁷-R¹⁰ (when present) is a bond,only one of R²¹-R²³ (when present) is a bond, and only one of R²⁴-R²⁵(when present) is a bond; for purposes of clarification, any one of thenitrogen atoms attached to R⁷ can serve as the point of attachment of R³to the isoquinoline ring; likewise, any one of the carbon atoms attachedto R⁸, R⁹, R¹⁰, R²¹, R²², R²³, R²⁴, or R²⁵ can serve as the point ofattachment of R³ to the isoquinoline ring.

In some embodiment, —(C₁₋₄ alkylene) is, optionally substituted with oneor more substituents as defined anywhere herein, wherein one or more Hare optionally replaced by D.

In some embodiment, —(C₁₋₄ alkylene) is, optionally substituted with oneor more halides (e.g., F, Cl, Br, I) or one or more unsubstituted —(C₁₋₃alkyl) (e.g., C_(2-3, 1-2, 1) alkyl).

In some embodiment, —(C₁₋₄ alkylene) is, optionally substituted with oneor more halides (e.g., F, Cl, Br, I) and one or more unsubstituted—(C₁₋₃ alkyl) (e.g., C_(2-3, 1-2, 1) alkyl).

In some embodiment, —(C₁₋₄ alkylene) is, optionally substituted with oneor more F or one or more Me.

In some embodiment, —(C₁₋₄ alkylene) is, optionally substituted with oneor more F and one or more Me.

In some embodiment, —(C₁₋₄ alkylene) is —CH₂—.

In some embodiment, —(C₁₋₄ alkylene) is —CD₂-.

In some embodiment, —(C₁₋₄ alkylene) is —CH₂CH₂—.

In some embodiment, —(C₁₋₄ alkylene) is —CH₂CH₂CH₂—.

In some embodiments, R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 (e.g., 1-4,1-3, 1-2, 1) R²⁷, -carbocyclyl optionally substituted with 1-5 (e.g.,1-4, 1-3, 1-2, 1) R²⁷, and —N(R³⁰)(R³¹); wherein —(C₁₋₄ alkylene) is,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R⁶ is selected from the group consisting of:

and q is 0 to 2, wherein one or more H on the heterocycle ring areoptionally replaced by D.

In some embodiments, R⁶ is selected from the group consisting of:

and q is 0 to 2, wherein one or more H on the heterocycle ring areoptionally replaced by D.

In some embodiments, R⁶ is

wherein n is 1-4 (e.g., 1-3, 1-2, 1), m is 0-2 (e.g., 0-1, 0) and each Zis independently selected from the group consisting of CR³² and N.

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is —N(R³)(R³¹).

In some embodiments, R⁶ is —NH(R³¹).

In some embodiments, R⁶ is selected from the group consisting of

wherein one or more H on the heterocycle ring are optionally replaced byD.

In some embodiments, R⁶ is —NMe(R³¹).

In some embodiments, R⁶ is selected from the group consisting of

wherein one or more H on the heterocycle ring are optionally replaced byD.

In some embodiments, R⁶ is selected from the group consisting of—CH₂phenyl substituted with 1-5 R⁴¹, —CH═CHphenyl optionally substitutedwith halide (e.g., F, Cl, Br, I), —(C₁₋₄ alkylene)_(p)heterocyclylsubstituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²⁷, -carbocyclylsubstituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R²⁸, and

wherein —(C₁₋₄ alkylene) is, optionally substituted with one or moresubstituents as defined anywhere herein; wherein n is 1-4 (e.g., 1-3,1-2, 1), m is 0-2 (e.g., 2, 1, 0) and each Z is independently selectedfrom the group consisting of CR³² and N.

In some embodiments, R⁶ is a selected from the group consisting of-phenyl substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R⁴² and 6-memberedheteroaryl optionally substituted with 1-6 (e.g., 1-5, 1-4, 1-3, 1-2, 1)R²⁹.

In some embodiments, R⁶ is a selected from the group consisting of-phenyl substituted with 1-2 R⁴² and pyridinyl optionally substitutedwith 1-2 R²⁹.

In some embodiments, R⁶ is a -phenyl substituted with 1-2 R⁴², whereinone or more H on the phenyl ring are replaced by D.

In some embodiments, R⁶ is a selected from the group consisting of-phenyl substituted with 1-2 R⁴² and pyridin-4-yl optionally substitutedwith 1-2 R²⁹.

In some embodiments, R³ is R

In certain embodiments, R⁹ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R⁹ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R⁷ is selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R⁷ is selected from the group consisting of H andMe.

In some embodiments, R⁷ is Me.

In some embodiments, R⁷ is CD₃.

In some embodiments, R⁸, R⁹, and R¹⁰ are independently selected from thegroup consisting of a single bond, H, and unsubstituted —(C₁₋₅ alkyl)(e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R⁸, R⁹, and R¹⁰ are independently selected from thegroup consisting of a single bond, H, and Me.

In some embodiments, R⁹ is a single bond connecting R³ to theisoquinoline ring and R⁸ and R¹⁰ are independently selected from thegroup consisting of H and Me.

In some embodiments, R⁹ is a single bond and R⁸ and R¹⁰ are both H.

In some embodiments, R³ is

In certain embodiments, R¹² is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R¹² is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R¹¹ is selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 35, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R¹¹ is selected from the group consisting of H andMe.

In some embodiments, R¹¹ is H.

In some embodiments, R¹¹ is Me.

In some embodiments, R¹¹ is CD₃.

In some embodiments, R¹², R¹³, and R¹⁴ are independently selected fromthe group consisting of a single bond, H, and unsubstituted —(C₁₋₅alkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R¹², R¹³, and R¹⁴ are independently selected fromthe group consisting of a single bond, H, and Me.

In some embodiments, R¹² is a single bond connecting R³ to theisoquinoline ring and R¹³ and R¹⁴ are independently selected from thegroup consisting of H and Me.

In some embodiments, R¹² is a single bond connecting R³ to theisoquinoline ring and R¹³ and R¹⁴ are both H.

In some embodiments, R¹² is a single bond connecting R³ to theisoquinoline ring; R¹³ is H, and R¹⁴ is Me.

In some embodiments, R³ is

In certain embodiments, R¹⁶ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R¹⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R¹⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R¹⁵ is selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R¹⁵ is selected from the group consisting of H andMe.

In some embodiments, R¹⁵ is H.

In some embodiments, R¹⁵ is Me.

In some embodiments, R¹⁵ is CD₃.

In some embodiments, R¹⁶ and R¹⁷ are independently selected from thegroup consisting of a single bond, H, and unsubstituted —(C₁₋₅ alkyl)(e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R¹⁶ and R¹⁷ are independently selected from thegroup consisting of a single bond, H, and Me.

In some embodiments, R¹⁷ is a single bond connecting R³ to theisoquinoline ring and R¹⁶ is selected from the group consisting of H andMe.

In some embodiments, R¹⁷ is a single bond connecting R³ to theisoquinoline ring and R¹⁶ is H.

In some embodiments, R³ is

In certain embodiments, R²⁰ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R²⁰ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R¹⁸ is selected from the group consisting of asingle bond, H, and unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R¹⁸ is selected from the group consisting of H andMe.

In some embodiments, R¹⁸ is H.

In some embodiments, R¹⁸ is Me.

In some embodiments, R¹⁸ is CD₃.

In some embodiments, R¹⁹ and R²⁰ are independently selected from thegroup consisting of a single bond, H, and unsubstituted —(C₁₋₅ alkyl)(e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R¹⁹ and R²⁰ are independently selected from thegroup consisting of a single bond, H, and Me.

In some embodiments, R²⁰ is a single bond connecting R³ to theisoquinoline ring and R¹⁹ is selected from the group consisting of H andMe.

In some embodiments, R²⁰ is a single bond connecting R³ to theisoquinoline ring and R¹⁹ is H.

In some embodiments, R³ is

In some embodiments, R³ is

and X is S.

In some embodiments, R³ is

and X is O.

In certain embodiments, R²⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R²⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R²¹, R²², and R²³ are independently selected fromthe group consisting of a single bond, H, and unsubstituted —(C₁₋₅alkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, X is O and R²¹, R²², and R²³ are independentlyselected from the group consisting of a single bond, H, and Me.

In some embodiments, X is O, R²¹ is a single bond connecting R³ to theisoquinoline ring and R²² and R²³ are independently selected from thegroup consisting of H and Me.

In some embodiments, X is O, R²¹ is a single bond connecting R³ to theisoquinoline ring and R²² and R²³ are both H.

In some embodiments, X is O, R²¹ is a single bond connecting R³ to theisoquinoline ring; R²² is H, and R²³ is Me.

In some embodiments, X is S and R²¹, R²², and R²³ are independentlyselected from the group consisting of a single bond, H, and Me.

In some embodiments, X is S, R²¹ is a single bond connecting R³ to theisoquinoline ring and R²² and R²³ are independently selected from thegroup consisting of H and Me.

In some embodiments, X is S, R²¹ is a single bond connecting R³ to theisoquinoline ring and R²² and R²³ are both H.

In some embodiments, X is S, R²¹ is a single bond connecting R³ to theisoquinoline ring; R²² is H, and R²³ is Me.

In some embodiments, R³ is

In some embodiments, R³ is

and X is S.

In some embodiments, R³ is

and X is O.

In certain embodiments, R³³ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R²⁴ and R²⁵ are independently selected from thegroup consisting of a single bond, H, and unsubstituted —(C₁₋₅ alkyl)(e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, X is O, R²⁴ and R²⁵ are independently selected fromthe group consisting of a single bond, H, and Me.

In some embodiments, X is O, R²⁵ is a single bond connecting R³ to theisoquinoline ring and R²⁴ is Me.

In some embodiments, X is O, R²⁵ is a single bond connecting R³ to theisoquinoline ring and R²⁴ is H.

In some embodiments, X is S, R²⁴ and R²⁵ are independently selected fromthe group consisting of a single bond, H, and Me.

In some embodiments, X is S, R²⁵ is a single bond connecting R³ to theisoquinoline ring and R²⁴ is Me.

In some embodiments, X is S, R²⁵ is a single bond connecting R³ to theisoquinoline ring and R²⁴ is H.

In some embodiments, each R²⁶ is independently unsubstituted —(C₁₋₅alkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, each R²⁶ is independently Me, Et, nPr, iPr, nBu,iBu, tBu.

In some embodiments, each R²⁷ is independently selected from the groupconsisting of halide (e.g., F, Cl, Br, I), unsubstituted —(C₁₋₅ alkyl)(e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl),unsubstituted —(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl), —OR³⁵,and —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-5(e.g., 1-4, 1-3, 1-2, 1) R³⁶; wherein —(C₁₋₄ alkylene) is, optionallysubstituted with one or more substituents as defined anywhere herein.

In some embodiments, each R²⁷ is independently selected from the groupconsisting of F, Me, Et, nPr, iPr, nBu, iBu, tBu, —CF₃, —OMe, -OEt,-heterocyclyl optionally substituted with 1-2 (e.g., 1) R³⁶ and—CH₂heterocyclyl optionally substituted with 1-2 (e.g., 1) R³⁶.

In some embodiments, each R²⁷ is independently selected from the groupconsisting of halide (e.g., F, Cl, Br, I) and —N(R⁴³)(R⁴⁴).

In some embodiments, if one or more R²⁷ is halide, at least one R²⁷ is—N(R⁴³)(R⁴⁴).

In some embodiments, each R²⁷ is F.

In some embodiments, R²⁷ is —N(R⁴³)(R⁴⁴).

In some embodiments, one R²⁷ is F and one R²⁷ is —N(R⁴³)(R⁴⁴).

In some embodiments, R²⁷ is —NMe₂; in some embodiments, R²⁷ is —NH(Me);in some embodiments, R²⁷ is —NH(Et); in some embodiments, R²⁷ is—NH(nPr); in some embodiments, R²⁷ is —NH(iPr); in some embodiments, R²⁷is —NH(nBu); in some embodiments, R²⁷ is —NH(iBu); in some embodiments,R²⁷ is —NH(tBu); wherein one or more H are optionally replaced by D.

In some embodiments, one R²⁷ is F and one R²⁷ is —NMe₂; in someembodiments, one R²⁷ is F and one R²⁷ is —NH(Me); in some embodiments,one R²⁷ is F and one R²⁷ is —NH(Et); in some embodiments, one R²⁷ is Fand one R²⁷ is —NH(nPr); in some embodiments, one R²⁷ is F and one R²⁷is —NH(iPr); in some embodiments, one R²⁷ is F and one R²⁷ is —NH(nBu);in some embodiments, one R²⁷ is F and one R²⁷ is —NH(iBu); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(tBu); wherein one or more Hare optionally replaced by D.

In some embodiments, R²⁷ is —NH(C₁₋₅ haloalkyl); in some embodiments,R²⁷ is —NH(C₁₋₄ haloalkyl); in some embodiments, R²⁷ is —NH(C₁₋₃haloalkyl); in some embodiments, R²⁷ is —NH(C₁₋₂ haloalkyl); in someembodiments, R²⁷ is —NH(CH₂CH₂F); in some embodiments, R²⁷ is—NH(CH₂CHF₂); in some embodiments, R²⁷ is —NH(CH₂CF₃); in someembodiments, R²⁷ is —NH(CH₂CH₂CH₂F); in some embodiments, R²⁷ is—NH(CH₂CH₂CHF₂); in some embodiments, R²⁷ is —NH(CH₂CH₂CF₃); in someembodiments, R²⁷ is —NH(CH(CH₂F)₂); in some embodiments, R²⁷ is—NH(CH(CHF₂)₂); in some embodiments, R²⁷ is —NH(CH(CF₃)₂); in someembodiments, R²⁷ is —N(C₁₋₅ haloalkyl)₂; in some embodiments, R²⁷ is—N(C₁₋₄ haloalkyl)₂; in some embodiments, R²⁷ is —N(C₁₋₃ haloalkyl)₂; insome embodiments, R²⁷ is —N(C₁₋₂ haloalkyl)₂; in some embodiments, R²⁷is —N(CH₂CH₂F)₂; in some embodiments, R²⁷ is —N(CH₂CHF₂)₂; in someembodiments, R²⁷ is —N(CH₂CF₃)₂; in some embodiments, R²⁷ is—N(CH₂CH₂CH₂F)₂; in some embodiments, R²⁷ is —N(CH₂CH₂CHF₂)₂; in someembodiments, R²⁷ is —N(CH₂CH₂CF₃)₂; in some embodiments, R²⁷ is—N(CH(CH₂F)₂)₂; in some embodiments, R²⁷ is —N(CH(CHF₂)₂)₂; in someembodiments, R²⁷ is —N(CH(CF₃)₂)₂; in some embodiments, R²⁷ is —NMe(C₁₋₅haloalkyl); in some embodiments, R²⁷ is —NMe(C₁₋₄ haloalkyl); in someembodiments, R²⁷ is —NMe(C₁₋₃ haloalkyl); in some embodiments, R²⁷ is—NMe(C₁₋₂ haloalkyl); in some embodiments, R²⁷ is —NMe(CH₂CH₂F); in someembodiments, R²⁷ is —NMe(CH₂CHF₂); in some embodiments, R²⁷ is—NMe(CH₂CF₃); in some embodiments, R²⁷ is —NMe(CH₂CH₂CH₂F); in someembodiments, R²⁷ is —NMe(CH₂CH₂CHF₂); in some embodiments, R²⁷ is—NMe(CH₂CH₂CF₃); in some embodiments, R²⁷ is —NMe(CH(CH₂F)₂); in someembodiments, R²⁷ is —NMe(CH(CHF₂)₂); in some embodiments, R²⁷ is—NMe(CH(CF₃)₂); wherein one or more H are optionally replaced by D.

In some embodiments, R²⁷ is —NH(CF₃).

In some embodiments, one R²⁷ is F and one R²⁷ is —NH(C₁₋₅ haloalkyl); insome embodiments, one R²⁷ is F and one R²⁷ is —NH(C₁₋₄ haloalkyl); insome embodiments, one R²⁷ is F and one R²⁷ is —NH(C₁₋₃ haloalkyl); insome embodiments, one R²⁷ is F and one R²⁷ is —NH(C₁₋₂ haloalkyl); insome embodiments, one R²⁷ is F and one R²⁷ is —NH(CH₂CH₂F); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH₂CHF₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH₂CF₃); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH₂CH₂CH₂F); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH₂CH₂CHF₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH₂CH₂CF₃); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH(CH₂F)₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH(CHF₂)₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NH(CH(CF₃)₂); in someembodiments, one R²⁷ is F and one R²⁷ is —N(C₁₋₅ haloalkyl)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(C₁₋₄ haloalkyl)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(C₁₋₃ haloalkyl)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(C₁₋₂ haloalkyl)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH₂CH₂F)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH₂CHF₂)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH₂CF₃)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH₂CH₂CH₂F)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH₂CH₂CHF₂)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH₂CH₂CF₃)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH(CH₂F)₂)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH(CHF₂)₂)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —N(CH(CF₃)₂)₂; in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(C₁₋₅ haloalkyl); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(C₁₋₄ haloalkyl); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(C₁₋₃ haloalkyl); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(C₁₋₂ haloalkyl); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH₂CH₂F); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH₂CHF₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH₂CF₃); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH₂CH₂CH₂F); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH₂CH₂CHF₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH₂CH₂CF₃); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH(CH₂F)₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH(CHF₂)₂); in someembodiments, one R²⁷ is F and one R²⁷ is —NMe(CH(CF₃)₂); wherein one ormore H are optionally replaced by D.

In some embodiments, one R²⁷ is F and one R²⁷ is —NH(CF₃).

In some embodiments, each R²⁸ is independently selected from the groupconsisting of —N(R³³)₂, —(C₁₋₄ alkylene)OR³⁵, —C(═O)(R³⁷), and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 (e.g., 1-4,1-3, 1-2, 1) R³⁶; wherein each —(C₁₋₄ alkylene) is independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R²⁸ is independently selected from the groupconsisting of —NH₂, —NH(Me), —NMe₂, —CH₂OH, —CH₂OMe, —C(═O)(R³⁷),-heterocyclyl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1)R³⁶, and —CH₂heterocyclyl optionally substituted with 1-5 (e.g., 1-4,1-3, 1-2, 1) R³⁶.

In some embodiments, each R²⁸ is independently selected from the groupconsisting of —NH₂, —NH(Me), —NMe₂, —CH₂OH, —CH₂OMe,

In some embodiments, each R²⁸ is —N(R³³)(R³⁴).

In some embodiments, R²⁸ is —NH₂.

In some embodiments, R²⁸ is —NMe₂; wherein one or more H are optionallyreplaced by D.

In some embodiments, R²⁸ is —NH(Me); wherein one or more H areoptionally replaced by D.

In some embodiments, R²⁸ is —NH(C_(1-s) haloalkyl); in some embodiments,R²⁸ is —NH(unsubstituted (C₁₋₄ haloalkyl)); in some embodiments, R²⁸ is—NH(C₁₋₃ haloalkyl); in some embodiments, R²⁸ is —NH(C₁₋₂ haloalkyl); insome embodiments, R²⁸ is —NH(CH₂CH₂F); in some embodiments, R²⁸ is—NH(CH₂CHF₂); in some embodiments, R²⁸ is —NH(CH₂CF₃); in someembodiments, R²⁸ is —NH(CH₂CH₂CH₂F); in some embodiments, R²⁸ is—NH(CH₂CH₂CHF₂); in some embodiments, R²⁸ is —NH(CH₂CH₂CF₃); in someembodiments, R²⁸ is —NH(CH(CH₂F)₂); in some embodiments, R²⁸ is—NH(CH(CHF₂)₂); in some embodiments, R²⁸ is —NH(CH(CF₃)₂); in someembodiments, R²⁸ is —N(C₁₋₅ haloalkyl)₂; in some embodiments, R²⁸ is—N(C₁₋₄ haloalkyl)₂; in some embodiments, R²⁸ is —N(C₁₋₃ haloalkyl)₂; insome embodiments, R²⁸ is —N(C₁₋₂ haloalkyl)₂; in some embodiments, R²⁸is —N(CH₂CH₂F)₂; in some embodiments, R²⁸ is —N(CH₂CHF₂)₂; in someembodiments, R²⁸ is —N(CH₂CF₃)₂; in some embodiments, R²⁸ is—N(CH₂CH₂CH₂F)₂; in some embodiments, R²⁸ is —N(CH₂CH₂CHF₂)₂; in someembodiments, R²⁸ is —N(CH₂CH₂CF₃)₂; in some embodiments, R²⁸ is—N(CH(CH₂F)₂)₂; in some embodiments, R²⁸ is —N(CH(CHF₂)₂)₂; in someembodiments, R²⁸ is —N(CH(CF₃)₂)₂; in some embodiments, R²⁸ is —NMe(C₁₋₅haloalkyl); in some embodiments, R²⁸ is —NMe(C₁₋₄ haloalkyl); in someembodiments, R²⁸ is —NMe(C₁₋₃ haloalkyl); in some embodiments, R²⁸ is—NMe(C₁₋₂ haloalkyl); in some embodiments, R²⁸ is —NMe(CH₂CH₂F); in someembodiments, R²⁸ is —NMe(CH₂CHF₂); in some embodiments, R²⁸ is—NMe(CH₂CF₃); in some embodiments, R²⁸ is —NMe(CH₂CH₂CH₂F); in someembodiments, R²⁸ is —NMe(CH₂CH₂CHF₂); in some embodiments, R²⁸ is—NMe(CH₂CH₂CF₃); in some embodiments, R²⁸ is —NMe(CH(CH₂F)₂); in someembodiments, R²⁸ is —NMe(CH(CHF₂)₂); in some embodiments, R²⁸ is—NMe(CH(CF₃)₂); wherein one or more H are optionally replaced by D.

In some embodiments, R²⁸ is —NH(CF₃).

In some embodiments, each R²⁸ is independently selected from the groupconsisting of —(C₁₋₄ alkylene)OR³⁵, —C(═O)(R³⁷), and —(C₁₋₄alkylene)_(p)heterocyclyl; wherein each —(C₁₋₄ alkylene) isindependently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, each R²⁹ is independently selected from the groupconsisting of unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl) andheterocyclyl optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1)R³⁶.

In some embodiments, each R²⁹ is independently selected from the groupconsisting of unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl), heterocyclyloptionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R³⁶, andN-oxide.

In some embodiments, R²⁹ is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, N-oxide,

wherein one or more H on the heterocycle ring are optionally replaced byD.

In some embodiments, R²⁹ is selected from the group consisting of

wherein one or more H on the heterocycle ring are optionally replaced byD.

In some embodiments, R³⁰ is attached to the nitrogen and is selectedfrom the group consisting of H and unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, In some embodiments, R³⁰ is attached to thenitrogen and is selected from the group consisting of H and Me.

In some embodiments, R³¹ is attached to the nitrogen and is heterocyclyloptionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R³⁸.

In some embodiments, In some embodiments, R³¹ is selected from the groupconsisting of

In some embodiments, each R³² is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl), unsubstituted—(C₂₋₅ alkenyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2) alkenyl),unsubstituted —(C₂₋₅ alkynyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2)alkynyl), and unsubstituted —(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl).

In some embodiments, each R³² is independently selected from the groupconsisting of H, Me, —CH₂F, —CHF₂, and —CF₃.

In some embodiments, In some embodiments, each R³² is H.

In some embodiments, R³³ is attached to the nitrogen and selected fromthe group consisting of H, unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl), unsubstituted—(C₂₋₅ alkenyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2) alkenyl),unsubstituted —(C₂₋₅ alkynyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2)alkynyl), and unsubstituted —(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl).

In some embodiments, R³³ is attached to the nitrogen and selected fromthe group consisting of H, unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl), unsubstituted—(C₂₋₅ alkenyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2) alkenyl),unsubstituted —(C₂₋₅ alkynyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2)alkynyl), and unsubstituted —(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl).

In some embodiments, R³³ is attached to the nitrogen and selected fromthe group consisting of H, unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl), unsubstituted—(C₂₋₅ alkenyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2) alkenyl), andunsubstituted —(C₂₋₅ alkynyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2)alkynyl).

In some embodiments, R³³ is selected from the group consisting of H, Me,Et, nPr, and iPr.

In some embodiments, R³³ is selected from the group consisting of H andMe.

In some embodiments, R³³ is selected from the group consisting of H, Me,Et, nPr, iPr, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH(CH₂F)₂, —CH(CHF₂)₂, and—CH(CF₃)₂.

In some embodiments, R³⁴ is attached to the nitrogen and is selectedfrom the group consisting of unsubstituted —(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 (e.g., 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 (e.g., 1-11,1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹, —(C₁₋₄alkylene)OR³⁵; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R³⁴ is attached to the nitrogen and is selectedfrom the group consisting of —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH(CH₂F)₂,—CH(CHF₂)₂, —CH(CF₃)₂,

—CH₂CH₂OH, and —CH₂CH₂OMe.

In some embodiments, each R³⁵ is independently selected from the groupconsisting of H and unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R³⁵ is selected from the group consisting of H andMe.

In some embodiments, each R³⁶ is selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl) andunsubstituted —(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl).

In some embodiments, each R³⁶ is selected from the group consisting ofMe, Et, nPr, iPr, —CH₂F, —CHF₂, and —CF₃.

In some embodiments, each R³⁶ is selected from the group consisting ofMe, —CH₂F, —CHF₂, and —CF₃.

In some embodiments, each R³⁶ is unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl);

In some embodiments, R³⁶ is selected from the group consisting of Me,Et, nPr, and iPr.

In some embodiments, R³⁶ is Me.

In some embodiments, each R³⁶ is independently selected from the groupconsisting of unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl) and N-oxide.

In some embodiments, R³⁶ is selected from the group consisting of Me,Et, nPr, iPr, and N-oxide.

In some embodiments, R³⁶ is selected from the group consisting of Me andN-oxide.

In some embodiments, R³⁶ is N-oxide.

In some embodiments, R³⁷ is -heterocyclyl optionally substituted withone or more halides (e.g., F, Cl, Br, I) or one or more unsubstituted—(C₁₋₅ alkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1)alkyl).

In some embodiments, R³⁷ is selected from the group consisting of

In some embodiments, each R³⁸ is independently selected from the groupconsisting of halide (e.g., F, Cl, Br, I) and unsubstituted —(C₁₋₅alkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl).

In some embodiments, R³⁸ is selected from the group consisting of F, Me,Et, nPr, and iPr.

In some embodiments, R³⁸ is Me.

In some embodiments, each R³⁹ is independently selected from the groupconsisting of halide (e.g., F, Cl, Br, I), unsubstituted —(C₁₋₅ alkyl)(e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl),unsubstituted —(C₂₋₅ alkenyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2)alkenyl), unsubstituted —(C₂₋₅ alkynyl) (e.g.,C_(3-5, 4-5, 2-4, 3-4, 2-3, 2) alkynyl), and unsubstituted —(C₁₋₅haloalkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1)haloalkyl), —CN, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁰; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R³⁹ is selected from the group consisting of F, Me,Et, nPr, and iPr.

In some embodiments, each R⁴⁰ is independently selected from the groupconsisting of halide (e.g., F, Cl, Br, I), unsubstituted —(C₁₋₅ alkyl)(e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl),unsubstituted —(C₂₋₅ alkenyl) (e.g., C_(3-5, 4-5, 2-4, 3-4, 2-3, 2)alkenyl), unsubstituted —(C₂₋₅ alkynyl) (e.g.,C_(3-5, 4-5, 2-4, 3-4, 2-3, 2) alkynyl), and unsubstituted —(C₁₋₅haloalkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1)haloalkyl), and —CN;

In some embodiments, R³⁹ is selected from the group consisting of F, Me,Et, nPr, and iPr.

In some embodiments, each R⁴¹ is independently selected from the groupconsisting of halide (e.g., F, Cl, Br, I) and —OMe.

In some embodiments, each R⁴² is independently selected from the groupconsisting of halide (e.g., F, Cl, Br, I), —OMe, and unsubstituted—(C₁₋₅ alkyl) (e.g., C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1)alkyl), wherein one or more H on the —OMe and/or alkyl are optionallyreplaced by D.

In some embodiments, R⁴² is selected from the group consisting of F, Cl,—OMe, and Me, wherein one or more H on the —OMe and/or Me are optionallyreplaced by D.

In some embodiments, R⁴³ is attached to the nitrogen and selected fromthe group consisting of H, unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl), andunsubstituted —(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl).

In some embodiments, R⁴⁴ is attached to the nitrogen and is selectedfrom the group consisting of H, unsubstituted —(C₁₋₅ alkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) alkyl), unsubstituted—(C₁₋₅ haloalkyl) (e.g.,C_(2-5, 3-5, 4-5, 2-4, 3-4, 2-3, 1-4, 1-3, 1-2, 1) haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 (e.g., 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 (e.g., 1-11,1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹, —(C₁₋₄alkylene)OR³⁵; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each p is independently 0 or 1.

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, there is the proviso that Formula I is not astructure selected from the group consisting of:

In some embodiments, each X is O or S.

Illustrative compounds of Formula (I) are shown in Table 1.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

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216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) atherapeutically effective amount of a compound provided herein, or itscorresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt; and (b) a pharmaceutically acceptablecarrier.

The compounds provided herein may also be useful in combination(administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with acombination of a compound of Formula (I) and other another active agentare colorectal cancer, ovarian cancer, chronic inflammation, diabeticretinopathy, pulmonary fibrosis, and osteoarthritis. For example, acompound of Formula (I) can be combined with one or morechemotherapeutic compounds.

In some embodiments, colorectal cancer can be treated with a combinationof a compound of Formula (I) and one or more of the following drugs:5-Fluorouracil (5-FU), which can be administered with the vitamin-likedrug leucovorin (also called folinic acid); capecitabine (XELODA®),irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples ofcombinations of these drugs which could be further combined with acompound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin),FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU,oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin).For rectal cancer, chemo with 5-FU or capecitabine combined withradiation may be given before surgery (neoadjuvant treatment).

In some embodiments, ovarian cancer can be treated with a combination ofa compound of Formula (I) and one or more of the following drugs:Topotecan, Liposomal doxorubicin (DOXIL®), Gemcitabine (GEMZAR®),Cyclophosphamide (CYTOXAN®), Vinorelbine (NAVELBINE®), Ifosfamide(IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine(XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed(ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®).Examples of combinations of these drugs which could be further combinedwith a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide,and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP(etoposide [VP-16], ifosfamide, and cisplatin).

In some embodiments, a compound of Formula (I) can be used to treatcancer in combination with any of the following methods: (a) Hormonetherapy such as aromatase inhibitors, LHRH [luteinizinghormone-releasing hormone] analogs and inhibitors, and others; (b)Ablation or embolization procedures such as radiofrequency ablation(RFA), ethanol (alcohol) ablation, microwave thermotherapy andcryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents suchas cisplatin and carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy usinganti-metabolites such as azathioprine and mercaptopurine; (e)Chemotherapy using plant alkaloids and terpenoids such as vincaalkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) andtaxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposideand docetaxel; (g) Chemotherapy using topoisomerase inhibitors such asirinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, andteniposide; (h) Chemotherapy using cytotoxic antibiotics such asactinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin,idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i)Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate(GLEEVEC®, also known as STI-571), Gefitinib (Iressa, also known asZD1839), Erlotinib (marketed as TARCEVA®), Bortezomib (VELCADE®),tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax inclinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib,Olaparib in clinical trials), PI3K inhibitors (e.g. perifosine in aphase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152,(AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818),MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g.PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy usingmonoclonal antibodies such as Rituximab (marketed as MABTHERA® orRITUXAN®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab(marketed as ERBITUX®), and Bevacizumab (marketed as AVASTIN®); and (k)radiation therapy.

In some embodiments, diabetic retinopathy can be treated with acombination of a compound of Formula (I) and one or more of thefollowing natural supplements: Bilberry, Butcher's broom, Ginkgo, Grapeseed extract, and Pycnogenol (Pine bark).

In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosiscan be treated with a combination of a compound of Formula (I) and oneor more of the following drugs: pirfenidone (pirfenidone was approvedfor use in 2011 in Europe under the brand name Esbriet®), prednisone,azathioprine, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan iscurrently being studied in patients with IPF, [The American Journal ofRespiratory and Critical Care Medicine (2011), 184(1), 92-9]),Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal ofPharmacology (2011), 163(1), 141-172], and anti-inflammatory agents suchas corticosteroids.

In some embodiments, a compound of Formula (I) can be used to treatidiopathic pulmonary fibrosis/pulmonary fibrosis in combination with anyof the following methods: oxygen therapy, pulmonary rehabilitation andsurgery.

In some embodiments, a compound of Formula (I) can be used to treatosteoarthritis in combination with any of the following methods: (a)Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen,naproxen, aspirin and acetaminophen; (b) physical therapy; (c)injections of corticosteroid medications; (d) injections of hyaluronicacid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine;(f) in combination with braces and/or shoe inserts or any device thatcan immobilize or support your joint to help you keep pressure off it(e.g., splints, braces, shoe inserts or other medical devices); (g)realigning bones (osteotomy); (h) joint replacement (arthroplasty); and(i) in combination with a chronic pain class.

In some embodiments, macular degeneration can be treated with acombination of a compound of Formula (I) and one or more of thefollowing drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®),Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) incombination with photodynamic therapy (PDT) or with any of the followingmethods: (a) in combination with laser to destroy abnormal blood vessels(photocoagulation); and (b) in combination with increased vitamin intakeof antioxidant vitamins and zinc.

In some embodiments, retinitis pigmentosa can be treated with acombination of a compound of Formula (I) and one or more of thefollowing drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurinor with any of the following methods: (a) with the Argus® II retinalimplant; and (b) with stem cell and/or gene therapy.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration, including, but not limited to, orally, subcutaneously,intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic devices. Insome embodiments, the administration method includes oral or parenteraladministration.

Compounds provided herein intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions may include solid, semi-solid, liquid,solutions, colloidal, liposomes, emulsions, suspensions, complexes,coacervates and aerosols. Dosage forms, such as, e.g., tablets,capsules, powders, liquids, suspensions, suppositories, aerosols,implants, controlled release or the like. They may be obtained, forexample, as solid plugs, powders, or films by methods such asprecipitation, crystallization, milling, grinding, supercritical fluidprocessing, coacervation, complex coacervation, encapsulation,emulsification, complexation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills (tablets and or capsules), transdermal (includingelectrotransport) patches, implants and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate.

The compounds can be administered either alone or in combination with aconventional pharmaceutical carrier, excipient or the like.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a compound as described herein in therange of 0.005% to 100% with the balance made up from non-toxic carriermay be prepared. The contemplated compositions may contain 0.001%-100%of a compound provided herein, in one embodiment 0.1-95%, in anotherembodiment 75-85%, in a further embodiment 20-80%. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London, UK. 2012).

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a compound provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or morecompounds provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. a compound provided herein andoptional pharmaceutical adjuvants in a carrier (e.g., water, saline,aqueous dextrose, glycerol, glycols, ethanol or the like) to form asolution, colloid, liposome, emulsion, complexes, coacervate orsuspension. If desired, the pharmaceutical composition can also containminor amounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, co-solvents, solubilizing agents, pH bufferingagents and the like (e.g., sodium acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/Kg to about 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/Kg to about 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.50 mg/Kg to about 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.75 mg/Kg to about 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.0 mg/Kg to about 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.25 mg/Kg to about 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.50 mg/Kg to about 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.75 mg/Kg to about 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 2.0 mg/Kg to about 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 3.0 mg/Kg to about 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 4.0 mg/Kg to about 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 5.0 mg/Kg to about 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration.

Injectables can be prepared in conventional forms, either as liquidsolutions, colloid, liposomes, complexes, coacervate or suspensions, asemulsions, or in solid forms suitable for reconstitution in liquid priorto injection. The percentage of a compound provided herein contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thepatient. However, percentages of active ingredient of 0.01% to 10% insolution are employable, and could be higher if the composition is asolid or suspension, which could be subsequently diluted to the abovepercentages.

In some embodiments, the composition will comprise about 0.1-10% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-5% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-4% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.15-3% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.2-2% of theactive agent in solution.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-96 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-72 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-48 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-24 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-12 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-6 hours.

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 300mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 100mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 10 mg/m² to about 50mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 50 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 75 mg/m² to about 175mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 100 mg/m² to about 150mg/m².

It is to be noted that concentrations and dosage values may also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularpatient, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

In one embodiment, the compositions can be administered to therespiratory tract (including nasal and pulmonary) e.g., through anebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For optimal delivery tothe nasal cavities, inhaled particle sizes of about 5 to about 100microns are useful, with particle sizes of about 10 to about 60 micronsbeing preferred. For nasal delivery, a larger inhaled particle size maybe desired to maximize impaction on the nasal mucosa and to minimize orprevent pulmonary deposition of the administered formulation. In someembodiments, aerosols intended for delivery to the lung are provided forinhalation through the nose or the mouth. For delivery to the lung,inhaled aerodynamic particle sizes of about less than 10 μm are useful(e.g., about 1 to about 10 microns). Inhaled particles may be defined asliquid droplets containing dissolved drug, liquid droplets containingsuspended drug particles (in cases where the drug is insoluble in thesuspending medium), dry particles of pure drug substance, drug substanceincorporated with excipients, liposomes, emulsions, colloidal systems,coacervates, aggregates of drug nanoparticles, or dry particles of adiluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formula (I) disclosed herein intendedfor respiratory delivery (either systemic or local) can be administeredas aqueous formulations, as non-aqueous solutions or suspensions, assuspensions or solutions in halogenated hydrocarbon propellants with orwithout alcohol, as a colloidal system, as emulsions, coacervates, or asdry powders. Aqueous formulations may be aerosolized by liquidnebulizers employing either hydraulic or ultrasonic atomization or bymodified micropump systems (like the soft mist inhalers, the Aerodose®or the AERx® systems). Propellant-based systems may use suitablepressurized metered-dose inhalers (pMDIs). Dry powders may use drypowder inhaler devices (DPIs), which are capable of dispersing the drugsubstance effectively. A desired particle size and distribution may beobtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I) disclosed hereincan be administered to the ear by various methods. For example, a roundwindow catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can beused.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the disclosure can be incorporated into agel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I) disclosed herein intendedfor delivery to the ear can be administered via an implanted pump anddelivery system through a needle directly into the middle or inner ear(cochlea) or through a cochlear implant stylet electrode channel oralternative prepared drug delivery channel such as but not limited to aneedle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddeddrug delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments the acidic or basic solid compound ofFormula (I) can be delivered from the reservoir of an external orinternal implanted pumping system.

Formulations of the disclosure also can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique ofinjecting a therapeutic agent behind the tympanic membrane into themiddle and/or inner ear. In one embodiment, the formulations describedherein are administered directly onto the round window membrane viatranstympanic injection. In another embodiment, the ion channelmodulating agent auris-acceptable formulations described herein areadministered onto the round window membrane via a non-transtympanicapproach to the inner ear. In additional embodiments, the formulationdescribed herein is administered onto the round window membrane via asurgical approach to the round window membrane comprising modificationof the crista fenestrae cochleae.

In some embodiments, the compounds of Formula (I) are formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG (like PEG ointments), and the like.

Suppositories for rectal administration of the drug (either as asolution, colloid, suspension or a complex) can be prepared by mixing acompound provided herein with a suitable non-irritating excipient thatis solid at ordinary temperatures but liquid at the rectal temperatureand will therefore melt or erode/dissolve in the rectum and release thecompound. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, poloxamers, mixtures of polyethyleneglycols of various molecular weights and fatty acid esters ofpolyethylene glycol. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter, is firstmelted.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the compoundprovided herein, the desired dissolution rate, cost considerations, andother criteria. In one of the embodiments, the solid composition is asingle unit. This implies that one unit dose of the compound iscomprised in a single, physically shaped solid form or article. In otherwords, the solid composition is coherent, which is in contrast to amultiple unit dosage form, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In one embodiment, the solid composition is a highly porous lyophilizedform. Such lyophilizates, sometimes also called wafers or lyophilizedtablets, are particularly useful for their rapid disintegration, whichalso enables the rapid dissolution of the compound.

On the other hand, for some applications the solid composition may alsobe formed as a multiple unit dosage form as defined above. Examples ofmultiple units are powders, granules, microparticles, pellets,mini-tablets, beads, lyophilized powders, and the like. In oneembodiment, the solid composition is a lyophilized powder. Such adispersed lyophilized system comprises a multitude of powder particles,and due to the lyophilization process used in the formation of thepowder, each particle has an irregular, porous microstructure throughwhich the powder is capable of absorbing water very rapidly, resultingin quick dissolution. Effervescent compositions are also contemplated toaid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with a compoundprovided herein so that the compound is located at the outer surface ofthe individual particles. In this type of system, the water-soluble lowmolecular weight excipient may be useful for preparing the cores of suchcoated particles, which can be subsequently coated with a coatingcomposition comprising the compound and, for example, one or moreadditional excipients, such as a binder, a pore former, a saccharide, asugar alcohol, a film-forming polymer, a plasticizer, or otherexcipients used in pharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with cancer. In another embodiment, the kitcan include a compound or composition as described herein and a labelthat indicates that the contents are to be administered to a patientwith one or more of hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonaryfibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis,psoriasis, scleroderma, mycotic and viral infections, bone and cartilagediseases, Alzheimer's disease, lung disease, bone/osteoporotic (wrist,spine, shoulder and hip) fractures, articular cartilage (chondral)defects, degenerative disc disease (or intervertebral discdegeneration), polyposis coli, bone density and vascular defects in theeye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia, Müllerian-duct regression and virilization, SERKALsyndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of one or more components of the Wnt pathway, whichmay include one or more Wnt proteins, and thus can be used to treat avariety of disorders and diseases in which aberrant Wnt signaling isimplicated, such as cancer and other diseases associated with abnormalangiogenesis, cellular proliferation, and cell cycling. Accordingly, thecompounds and compositions provided herein can be used to treat cancer,to reduce or inhibit angiogenesis, to reduce or inhibit cellularproliferation, to correct a genetic disorder, and/or to treat aneurological condition/disorder/disease due to mutations ordysregulation of the Wnt pathway and/or of one or more of Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,scleroderma, mycotic and viral infections, bone and cartilage diseases,neurological conditions/diseases such as Alzheimer's disease,amyotrophic lateral sclerosis (ALS), motor neuron disease, multiplesclerosis or autism, lung disease, bone/osteoporotic (wrist, spine,shoulder and hip) fractures, polyposis coli, bone density and vasculardefects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familialexudative vitreoretinopathy, retinal angiogenesis, early coronarydisease, tetra-amelia, Müllerian-duct regression and virilization,SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutivelyactivated in a variety of cancers including, for example, colon cancer,hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer,pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly,the compounds and compositions described herein may be used to treatthese cancers in which the Wnt pathway is constitutively activated. Incertain embodiments, the cancer is chosen from hepatocellular carcinoma,colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositionsdescribed herein.

More particularly, cancers that may be treated by the compounds,compositions and methods described herein include, but are not limitedto, the following:

1) Breast cancers, including, for example ER⁺ breast cancer, ER⁻ breastcancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such asfibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumorssuch as large duct papillomas; carcinomas of the breast including insitu (noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma; and miscellaneous malignant neoplasms. Further examples ofbreast cancers can include luminal A, luminal B, basal A, basal B, andtriple negative breast cancer, which is estrogen receptor negative(ER⁻), progesterone receptor negative, and her2 negative (her2-). Insome embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g.,squamous cell, undifferentiated small cell, undifferentiated large cell,and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchialadenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of theesophagus, e.g., squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma,lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; cancers of the large bowel, e.g.,adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, andleiomyoma.

5) Genitourinary tract cancers, including, for example, cancers of thekidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,and leukemia; cancers of the bladder and urethra, e.g., squamous cellcarcinoma, transitional cell carcinoma, and adenocarcinoma; cancers ofthe prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis,e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellularcarcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma;hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochrondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

8) Nervous system cancers, including, for example, cancers of the skull,e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans;cancers of the meninges, e.g., meningioma, meningiosarcoma, andgliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, andcongenital tumors; and cancers of the spinal cord, e.g., neurofibroma,meningioma, glioma, and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus,e.g., endometrial carcinoma; cancers of the cervix, e.g., cervicalcarcinoma, and pre tumor cervical dysplasia; cancers of the ovaries,e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors,Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma;cancers of the vulva, e.g., squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of thevagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopiantubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood,e.g., acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin'slymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom'smacroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignantmelanoma and metastatic melanoma, basal cell carcinoma, squamous cellcarcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, and scleroderma.

12) Adrenal gland cancers, including, for example, neuroblastoma.

More particularly, tumors of the central nervous system that may betreated by the compounds, compositions and methods described hereininclude:

1) Astrocytic tumors, e.g., diffuse astrocytoma (fibrillary,protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma,glioblastoma multiforme (giant cell glioblastoma and gliosarcoma),pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphicxanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosiscerebri.

2) Oligodendroglial tumors, e.g., oligodendroglioma and anaplasticoligodendroglioma.

3) Oligoastrocytic tumors, e.g., oligoastrocytoma and anaplasticoligoastrocytoma.

4) Ependymal tumors, e.g., subependymoma, myxopapillary ependymoma,ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic(malignant) ependymoma.

5) Choroid plexus tumors, e.g., choroid plexus papilloma, atypicalchoroid plexus papilloma, and choroid plexus carcinoma.

6) Neuronal and mixed neuronal-glial tumors, e.g., gangliocytoma,ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplasticgangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplasticinfantile astrocytoma/ganglioglioma, central neurocytoma, anaplasticganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma,Papillary glioneuronal tumor, Rosette-forming glioneuronal tumor of thefourth ventricle, and paraganglioma of the filum terminale.

7) Pineal tumors, e.g., pineocytoma, pineoblastoma, papillary tumors ofthe pineal region, and pineal parenchymal tumor of intermediatedifferentiation.

8) Embryonal tumors, e.g., medulloblastoma (medulloblastoma withextensive nodularity, anaplastic medulloblastoma, desmoplastic, largecell, melanotic, medullomyoblastoma), medulloepithelioma, supratentorialprimitive neuroectodermal tumors, and primitive neuroectodermal tumors(PNETs) such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma,and atypical teratoid/rhabdoid tumor.

9) Neuroblastic tumors, e.g., olfactory (esthesioneuroblastoma),olfactory neuroepithelioma, and neuroblastomas of the adrenal gland andsympathetic nervous system.

10) Glial tumors, e.g., astroblastoma, chordoid glioma of the thirdventricle, and angiocentric glioma.

11) Tumors of cranial and paraspinal nerves, e.g., schwannoma,neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.

12) Tumors of the meninges such as tumors of meningothelial cells, e.g.,meningioma (atypical meningioma and anaplastic meningioma); mesenchymaltumors, e.g., lipoma, angiolipoma, hibernoma, liposarcoma, solitaryfibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma,leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma,chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma,epithelioid hemangioendothelioma, haemangiopericytoma, anaplastichaemangiopericytoma, angiosarcoma, Kaposi Sarcoma, and Ewing Sarcoma;primary melanocytic lesions, e.g., diffuse melanocytosis, melanocytoma,malignant melanoma, meningeal melanomatosis; and hemangioblastomas.

13) Tumors of the hematopoietic system, e.g., malignant Lymphomas,plasmocytoma, and granulocytic sarcoma.

14) Germ cell tumors, e.g., germinoma, embryonal carcinoma, yolk sactumor, choriocarcinoma, teratoma, and mixed germ cell tumors.

15) Tumors of the sellar region, e.g., craniopharyngioma, granular celltumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used asanti-angiogenesis agents and as agents for modulating and/or inhibitingthe activity of protein kinases, thus providing treatments for cancerand other diseases associated with cellular proliferation mediated byprotein kinases. For example, the compounds described herein can inhibitthe activity of one or more kinases. Accordingly, provided herein is amethod of treating cancer or preventing or reducing angiogenesis throughkinase inhibition.

In addition, and including treatment of cancer, the compounds andcompositions described herein can function as cell-cycle control agentsfor treating proliferative disorders in a patient. Disorders associatedwith excessive proliferation include, for example, cancers, scleroderma,immunological disorders involving undesired proliferation of leukocytes,and restenosis and other smooth muscle disorders. Furthermore, suchcompounds may be used to prevent de-differentiation of post-mitotictissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

-   -   a variety of cancers, including, but not limited to, carcinoma,        hematopoietic tumors of lymphoid lineage, hematopoietic tumors        of myeloid lineage, tumors of mesenchymal origin, tumors of the        central and peripheral nervous system and other tumors including        melanoma, seminoma and Kaposi's sarcoma.    -   a disease process which features abnormal cellular        proliferation, e.g., benign prostatic hyperplasia, familial        adenomatosis polyposis, neurofibromatosis, atherosclerosis,        arthritis, glomerulonephritis, restenosis following angioplasty        or vascular surgery, inflammatory bowel disease, transplantation        rejection, endotoxic shock, and fungal infections. Fibrotic        disorders such as skin fibrosis; scleroderma; progressive        systemic fibrosis; lung fibrosis; muscle fibrosis; kidney        fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic        scar formation; uterine fibrosis; renal fibrosis; cirrhosis of        the liver, liver fibrosis; fatty liver disease (FLD); adhesions,        such as those occurring in the abdomen, pelvis, spine or        tendons; chronic obstructive pulmonary disease; fibrosis        following myocardial infarction; pulmonary fibrosis; fibrosis        and scarring associated with diffuse/interstitial lung disease;        central nervous system fibrosis, such as fibrosis following        stroke; fibrosis associated with neuro-degenerative disorders        such as Alzheimer's Disease or multiple sclerosis; fibrosis        associated with proliferative vitreoretinopathy (PVR);        restenosis; endometriosis; ischemic disease and radiation        fibrosis.    -   defective apoptosis-associated conditions, such as cancers        (including but not limited to those types mentioned herein),        viral infections (including but not limited to herpesvirus,        poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus),        prevention of AIDS development in HIV-infected individuals,        autoimmune diseases (including but not limited to systemic lupus        erythematosus, rheumatoid arthritis, sepsis, ankylosing        spondylitis, psoriasis, scleroderma, autoimmune mediated        glomerulonephritis, inflammatory bowel disease and autoimmune        diabetes mellitus), neuro-degenerative disorders (including but        not limited to Alzheimer's disease, lung disease, amyotrophic        lateral sclerosis, retinitis pigmentosa, Parkinson's disease,        AIDS-related dementia, spinal muscular atrophy and cerebellar        degeneration), myelodysplastic syndromes, aplastic anemia,        ischemic injury associated with myocardial infarctions, stroke        and reperfusion injury, arrhythmia, atherosclerosis,        toxin-induced or alcohol related liver diseases, hematological        diseases (including but not limited to chronic anemia and        aplastic anemia), degenerative diseases of the musculoskeletal        system (including but not limited to osteoporosis and        arthritis), tendinopathies such as tendinitis and tendinosis,        aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple        sclerosis, kidney diseases and cancer pain.    -   genetic diseases due to mutations in Wnt signaling components,        such as polyposis coli, bone density and vascular defects in the        eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial        exudative vitreoretinopathy, retinal angiogenesis, early        coronary disease, tetra-amelia, Müllerian-duct regression and        virilization, SERKAL syndrome, type II diabetes, Fuhrmann        syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,        odonto-onycho-dermal dysplasia, obesity, split-hand/foot        malformation, caudal duplication, tooth agenesis, Wilms tumor,        skeletal dysplasia, focal dermal hypoplasia, autosomal recessive        anonychia, neural tube defects, alpha-thalassemia (ATRX)        syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome,        Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie        disease and Rett syndrome.

The compounds and compositions provided herein have been found topossess immunomodulatory activities and are expected to control theinnate and adaptive immune system (e.g. macrophages, microglia,dendritic cells, B and T cells) and suppress pro-inflammatory cytokinerelease (e.g. TNF, IL-6, IL-1, IFN) which is well known to be involvedin chronic inflammation in a wide variety of disease areas. Thereforecompounds and compositions provided herein can used to treat chronicinflammation associated with disorders and diseases including but notlimited to eye disorders, joint pain, arthritis (rheumatoid, osteo,psoriatic gout), cancers (colon, breast, lung, pancreas, and others),gastrointestinal disorders (ulcerative colitis and inflammatory boweldiseases), pulmonary disorders (chronic obstructive pulmonary disorderand asthma), allergies, skin disorders (atopic dermatitis andpsoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heartdisease, myocarditis, stroke, lupus, and neurological disorders such asmultiple sclerosis, Parkinson's and dementia including Alzheimer'sdisease.

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of the enzyme DYRK1A, and thus can be used to treat avariety of disorders and diseases associated with tau protein, amyloid,alpha-synuclein, TDP-43 or FUS pathology including, but not limited to,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), down syndrome,frontotemporal dementia (FTD) including FTD with Parkinsonism-17(FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD inpatients with motor neuron disease (MND) (typically amyotrophic lateralsclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (alsocalled corticobasal ganglionic degeneration), progressive supranuclearpalsy, primary progressive aphasia (PPA), globular glial tauopathy(GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease),myotonic dystrophy type 2 (DM2) (also called proximal myotonicmyopathy), Guam complex, argyrophilic grain disease, dementiapugilistica, post-encephalitic parkinsonism, Lewy body dementia,Parkinson's disease, Pick's disease, and additional diseases withpronounced neurodegeneration such as autism, dementia, epilepsy,Huntington's disease, multiple sclerosis; diseases and disordersassociated with acquired brain injury such as chronic traumaticencephalopathy, traumatic brain injury, tumor, and stroke.

Non-limiting examples of neurological disorders (e.g., neurologicalconditions and neurological diseases) which can be treated with thecompounds and compositions provided herein include Alzheimer's disease,aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attentiondeficit hyperactivity disorder, auditory processing disorder, autism,alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury,Canavan disease, carpal tunnel syndrome, causalgia, central painsyndrome, central pontine myelinolysis, centronuclear myopathy, cephalicdisorder, cerebral aneurysm, cerebral arteriosclerosis, cerebralatrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis,cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiarimalformation, chronic fatigue syndrome, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowrysyndrome, complex regional pain syndrome, compression neuropathy,congenital facial diplegia, corticobasal degeneration, cranialarteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulativetrauma disorder, Cushing's syndrome, cytomegalic inclusion body disease(CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome,Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phasesyndrome, dementia, dermatomyositis, developmental dyspraxia, diabeticneuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia,dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome,encephalitis, encephalocele, encephalotrigeminal angiomatosis,encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor,Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrileseizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville'ssyndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis,giant cell inclusion disease, globoid cell leukodystrophy, gray matterheterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy,Hallervorden-Spatz disease, hemifacial spasm, hereditary spasticparaplegia, heredopathia atactica polyneuritiformis, herpes zosteroticus, herpes zoster, Hirayama syndrome, holoprosencephaly,Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism,hypoxia, immune-mediated encephalomyelitis, inclusion body myositis,incontinentia pigmenti, infantile phytanic acid storage disease,infantile Refsum disease, infantile spasms, inflammatory myopathy,intracranial cyst, intracranial hypertension, Joubert syndrome, Karaksyndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome,Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru,Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffnersyndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease,Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy bodydementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease,lumbar disc disease, lumbar spinal stenosis, Lyme disease,Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly,macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere'sdisease, meningitis, Menkes disease, metachromatic leukodystrophy,microcephaly, micropsia, Miller Fisher syndrome, misophonia,mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motorneuron disease, motor skills disorder, Moyamoya disease,mucopolysaccharidoses, multi-infarct dementia, multifocal motorneuropathy, multiple sclerosis, multiple system atrophy, musculardystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclasticdiffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus,myopathy, myotubular myopathy, myotonia congenital, narcolepsy,neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus,neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease,O'Sullivan-McLeod syndrome, occipital Neuralgia, occult SpinalDysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy,opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension,palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita,paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome,Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy,photic sneeze reflex, phytanic acid storage disease, Pick's disease,polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome,postherpetic neuralgia (PHN), postural hypotension, Prader-Willisyndrome, primary lateral sclerosis, prion diseases, progressivehemifacial atrophy, progressive multifocal leukoencephalopathy,progressive supranuclear palsy, pseudotumor cerebri, Ramsay Huntsyndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome typeIII, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsumdisease, restless legs syndrome, retrovirus-associated myelopathy, Rettsyndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome,Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease,schizencephaly, sensory integration dysfunction, septo-optic dysplasia,Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome,spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome,Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacutesclerosing panencephalitis, subcortical arteriosclerotic encephalopathy,superficial siderosis, Sydenham's chorea, syncope, synesthesia,syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardivedysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus,tethered spinal cord syndrome, Thomsen disease, thoracic outletsyndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxicencephalopathy, transient ischemic attack, transmissible spongiformencephalopathies, transverse myelitis, tremor, trigeminal neuralgia,tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis,ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis(VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome,Williams syndrome, Wilson's disease, and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition ofthe development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiments, the disclosure provides a method for treating adisease or disorder associated with aberrant cellular proliferation byadministering to a patient in need of such treatment an effective amountof one or more of the compounds of Formula (I), in combination(simultaneously or sequentially) with at least one other agent.

In some embodiments, the disclosure provides a method of treating orameliorating in a patient a disorder or disease selected from the groupconsisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis(IPF), degenerative disc disease, bone/osteoporotic fractures, bone orcartilage disease, and osteoarthritis, the method comprisingadministering to the patient a therapeutically effective amount of acompound according to Formula (I), or a pharmaceutically acceptable saltthereof.

In some embodiments, the disclosure provides a method of treating orameliorating in a patient a disorder or disease selected from the groupconsisting of: chronic inflammation, systemic inflammation, diabetes,cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF),degenerative disc disease, bone/osteoporotic fractures, a bone orcartilage disease, a neurological condition/disorder/disease,osteoarthritis, lung disease, a fibrotic disorder.

In some embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In some embodiments, the method of treats a disorder or disease in whichaberrant Wnt signaling is implicated in a patient, the method comprisesadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is the pain andinflammation associated with cancer.

In some embodiments, the disorder or disease is the pain andinflammation associated with a joint.

In some embodiments, the disorder or disease is the pain andinflammation associated with the knee.

In some embodiments, the disorder or disease is the pain andinflammation associated with the hip.

In some embodiments, the disorder or disease is the pain andinflammation associated with the shoulder.

In some embodiments, the disorder or disease is the pain andinflammation associated with arthritis.

In some embodiments, the disorder or disease is the pain andinflammation associated with gastrointestinal disorders.

In some embodiments, the disorder or disease is the pain andinflammation associated with pulmonary disorders.

In some embodiments, the disorder or disease is the pain andinflammation associated with allergies.

In some embodiments, the disorder or disease is the pain andinflammation associated with skin disorders.

In some embodiments, the disorder or disease is the pain andinflammation associated with diabetes.

In some embodiments, the disorder or disease is the pain andinflammation associated with pancreatitis.

In some embodiments, the disorder or disease is the pain andinflammation associated with tendonitis.

In some embodiments, the disorder or disease is the pain andinflammation associated with heart disease.

In some embodiments, the disorder or disease is the pain andinflammation associated with lupus.

In some embodiments, the disorder or disease is the pain andinflammation associated with a neurological disorder.

In some embodiments, the disorder or disease is the pain andinflammation associated with multiple sclerosis.

In some embodiments, the disorder or disease is the pain andinflammation associated with Parkinson's.

In some embodiments, the disorder or disease is cancer.

In some embodiments, the disorder or disease is systemic inflammation.

In some embodiments, the disorder or disease is metastatic melanoma.

In some embodiments, the disorder or disease is fatty liver disease.

In some embodiments, the disorder or disease is liver fibrosis.

In some embodiments, the disorder or disease is tendon regeneration.

In some embodiments, the disorder or disease is diabetes.

In some embodiments, the disorder or disease is degenerative discdisease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is diabetic retinopathy.

In some embodiments, the disorder or disease is pulmonary fibrosis.

In some embodiments, the disorder or disease is idiopathic pulmonaryfibrosis (IPF).

In some embodiments, the disorder or disease is degenerative discdisease.

In some embodiments, the disorder or disease is rheumatoid arthritis.

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viralinfection.

In some embodiments, the disorder or disease is a bone or cartilagedisease.

In some embodiments, the disorder or disease is a neurological disorder.

In some embodiments, the disorder or disease is Alzheimer's disease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease.

In some embodiments, the disorder or disease is a genetic disease causedby mutations in Wnt signaling components, wherein the genetic disease isselected from: polyposis coli, osteoporosis-pseudoglioma syndrome,familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia syndrome, Müllerian-duct regression andvirilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen from: hepatocellularcarcinoma, colon cancer, breast cancer, pancreatic cancer, chronicmyeloid leukemia (CML), chronic myelomonocytic leukemia, chroniclymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocyticleukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-smallcell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer,neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostatecancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer—basal and squamous cell, skin cancer—melanoma, small intestinecancer, stomach (gastric) cancers, testicular cancer, thymus cancer,thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer,laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma,gestational trophoblastic disease, gastrointestinal stromal tumor,gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer(melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrialcancer, colorectal cancer, cervical cancer, brain or spinal cord tumor,bone metastasis, bone cancer, bladder cancer, bile duct cancer, analcancer and adrenal cortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is chronic myeloid leukemia (CML).

In some embodiments, the cancer is chronic myelomonocytic leukemia.

In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach (gastric) cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

In some embodiments, the disorder or disease is a neurologicalcondition/disorder/disease, wherein the neurologicalcondition/disorder/disease is selected from: Alzheimer's disease,frontotemporal dementias, dementia with Lewy bodies, prion diseases,Parkinson's disease, Huntington's disease, progressive supranuclearpalsy, corticobasal degeneration, multiple system atrophy, amyotrophiclateral sclerosis (ALS), inclusion body myositis, autism, degenerativemyopathies, diabetic neuropathy, other metabolic neuropathies, endocrineneuropathies, orthostatic hypotension, multiple sclerosis andCharcot-Marie-Tooth disease.

In some embodiments, the disorder or disease is a neurologicalcondition/disorder/disease associated with tau protein, amyloid,alpha-synuclein pathology, Tar DNA-binding Protein of 43 KDa (TDP-43),Prion protein PrP or fused in sarcoma (FUS).

In some embodiments, the disorder or disease is a neurologicalcondition/disorder/disease, wherein the neurologicalcondition/disorder/disease is selected from the group consisting of:Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Down Syndrome,Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy bodydementia, Parkinson's Disease, Pick's Disease, and additional diseaseswith pronounced neurodegeneration such as Autism, Dementia, Epilepsy,Huntington's Disease, Multiple Sclerosis; diseases and disordersassociated with acquired brain injury such as Chronic TraumaticEncephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

In some embodiments, the disorder or disease is a fibrotic disorder,wherein the fibrotic disorder is selected from the group consisting of:skin fibrosis; scleroderma; progressive systemic fibrosis; lungfibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis;glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renalfibrosis; cirrhosis of the liver, liver fibrosis; adhesions; chronicobstructive pulmonary disease; fibrosis following myocardial infarction;pulmonary fibrosis; fibrosis and scarring associated withdiffuse/interstitial lung disease; central nervous system fibrosis;fibrosis associated with proliferative vitreoretinopathy (PVR);restenosis; endometriosis; ischemic disease, and radiation fibrosis.

In some embodiments, the disorder or disease is chronic inflammationassociated with eye disorders, joint pain, arthritis (rheumatoid, osteo,psoriatic gout), cancers (colon, breast, lung, pancreas, and others),gastrointestinal disorders (ulcerative colitis and inflammatory boweldiseases), pulmonary disorders (chronic obstructive pulmonary disorderand asthma), allergies, skin disorders (atopic dermatitis andpsoriasis), diabetes, pancreatitis, tendonitis, hepatitis, heartdisease, myocarditis, stroke, lupus, and neurological disorders such asmultiple sclerosis, Parkinson's and dementia including Alzheimer'sdisease.

In some embodiments, a compound of Formula (I) inhibits DYRK1A.

In some embodiments, a compound of Formula (I) inhibits GSK3.

In some embodiments, a compound of Formula (I) inhibits GSK3β.

In some embodiments, a compound of Formula (I) inhibits DYRK1A andGSK3β.

In some embodiments, the compound of Formula (I) inhibits one or moreproteins in the Wnt pathway.

In some embodiments, the compound of Formula (I) inhibits signalinginduced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2,WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A,WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, the compound of Formula (I) inhibits a kinaseactivity.

In some embodiments, the method treats a disease or disorder mediated bythe Wnt pathway in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) inhibits one or moreWnt proteins.

In some embodiments, the method treats a disease or disorder mediated bykinase activity in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease or disorder comprises tumor growth,cell proliferation, or angiogenesis.

In some embodiments, the method inhibits the activity of a proteinkinase receptor, the method comprises contacting the receptor with aneffective amount of a compound (or compounds) of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient; the method comprisesadministering to the patient a therapeutically effective amount of acompound (or compounds) of Formula (I), or a pharmaceutically acceptablesalt thereof.

In some embodiments, the method prevents or reduces angiogenesis in apatient; the method comprises administering to the patient atherapeutically effective amount of a compound (or compounds) of Formula(I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellularproliferation in a patient; the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient, the method comprisesadministering to the patient a pharmaceutical composition comprising oneor more of the compounds of Formula (I) in combination with apharmaceutically acceptable carrier and one or more other agents.

Moreover, the compounds and compositions, for example, as inhibitors ofthe cyclin-dependent kinases (CDKs), can modulate the level of cellularRNA and DNA synthesis and therefore are expected to be useful in thetreatment of viral infections such as HIV, human papilloma virus, herpesvirus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and thelike.

Compounds and compositions described herein can inhibit the kinaseactivity of, for example, CDK/cyclin complexes, such as those active inthe G₀ or G₁ stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, see, e.g.,WO 2001/053268 and WO 2005/009997. For example, the activity of acompound may be tested using one or more of the test methods outlinedbelow.

In one example, tumor cells may be screened for Wnt independent growth.In such a method, tumor cells of interest are contacted with a compound(i.e. inhibitor) of interest, and the proliferation of the cells, e.g.by uptake of tritiated thymidine, is monitored. In some embodiments,tumor cells may be isolated from a candidate patient who has beenscreened for the presence of a cancer that is associated with a mutationin the Wnt signaling pathway. Candidate cancers include, withoutlimitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biologicalactivity, e.g. stabilization of γ-catenin and promoting growth of stemcells. Assays for biological activity of Wnt include stabilization ofβ-catenin, which can be measured, for example, by serial dilutions of acandidate inhibitor composition. An exemplary assay for Wnt biologicalactivity contacts a candidate inhibitor with cells containingconstitutively active Wnt/β-catenin signaling. The cells are culturedfor a period of time sufficient to stabilize β-catenin, usually at leastabout 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, thentransferred to nitrocellulose and probed with antibodies specific forγ-catenin.

In a further example, the activity of a candidate compound can bemeasured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell(1997), 88(6), 747-756).

In another example, in vitro assays for DYRK1A biological activity maybe used, e.g. regulation of microtubule-associated protein tau(MAPT/Tau) phosphorylation in neuronal cell line such as the humanSH-SY5Y neuroblastoma cell line. Assays for DYRK1A-regulated level ofphosphorylation can include monitoring levels of basal pSer396 Tau,which can be measured, for example, by serial dilutions of a candidateinhibitor composition using a ten micromolar top concentration anddetected by ELISA or Western Blotting. An exemplary assay forDYRK-1A-regulated phosphorylation uses the SH-SY5Y cells cultured in a96 well plate format for a period of time sufficient to stabilizemicrotubules and Tau phosphorylation, usually at least 2 days, thentreated with a ⅓ serial dilution of compounds overnight and lysed. Thecell lysate is resolved by SDS PAGE, then transferred to nitrocelluloseand probed with an antibody specific for pSer396 Tau. Thechemiluminescence signal for HRP-linked antibodies used in westernblotting is detected using a Carestream Image Station and blotdensitometry for pSer396 and beta-actin are analyzed using ImageJ (NIH).

In a further example, the activity of a candidate compound can bemeasured by ELISA by adding the lysate mentioned above onto totalTau-coated plates and detected with a specific pSer396 antibody.Colorimetric detection of ELISA signal is performed by Cytation3 platereader (Biotek).

To further illustrate this disclosure, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the disclosure. Variations of these exampleswithin the scope of the claims are within the purview of one skilled inthe art and are considered to fall within the scope of the disclosure asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the disclosure without exhaustive examples.

EXAMPLES

Compound Preparation

The starting materials used in preparing the compounds of the disclosureare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand functionality related to the compounds claimed herein are generallydescribed in the literature. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure 7^(th) Ed., JohnWiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations: AGuide to Functional Group Transformations, 2nd Ed., John Wiley & Sons(1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in P. Wuts Greene's ProtectiveGroups in Organic Synthesis, 5th Ed., John Wiley & Sons (2014),incorporated herein by reference in its entirety.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the disclosure. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the disclosure.

(¹H) nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHzfor ¹H or Avance™ DRX500, 500 MHz for ¹H) or Varian NMR spectrometer(Mercury 400BB, 400 MHz for ¹H). Peak positions are expressed in partsper million (ppm) downfield from tetramethylsilane. The peakmultiplicities are denoted as follows, s, singlet; d, doublet; t,triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep,septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets ofdoublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td,triplet of doublets; dq, doublet of quartets; m, multiplet.

The following abbreviations have the indicated meanings:

-   -   brine=saturated aqueous sodium chloride    -   CDCl₃=deuterated chloroform    -   DCE=dichloroethane    -   DCM=dichloromethane    -   DIPEA=N,N-diisopropylethylamine    -   DMA=dimethylacetamide    -   DMAP=4-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO-d₆=deuterated dimethylsulfoxide    -   ESIMS=electron spray mass spectrometry    -   EtOAc=ethyl acetate    -   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo        [4,5-b]pyridinium 3-oxid hexafluorophosphate    -   HCl=hydrochloric acid    -   HOAc=acetic acid    -   ISCO=Teledyne ISCO, Inc brand CombiFlash® Rf 200    -   KOAc=potassium acetate    -   LC/MS=Liquid chromatography-mass spectrometry    -   MCPBA=meta-chloroperoxybenzoic acid    -   MeCN=acetonitrile    -   MeOH=methanol    -   MgSO₄=magnesium sulfate    -   MW=microwave irradiation    -   NaBH₃CN=sodium cyanoborohydride    -   NaHCO₃=sodium bicarbonate    -   Na(OAc)₃BH=Sodium triacetoxyborohydride    -   NMR=nuclear magnetic resonance    -   ON=overnight    -   Pd(dppf)Cl₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride    -   Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)    -   r.t.=room temperature    -   SPhos Pd        G4=Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)    -   TBAF=tetra-n-butylammonium fluoride,    -   TEA=triethylamine    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the disclosure will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. The skilled artisan is thoroughly equipped to prepare thesecompounds by those methods given the literature and this disclosure. Thecompound numberings used in the synthetic schemes depicted below aremeant for those specific schemes only, and should not be construed as orconfused with same numberings in other sections of the application.Unless otherwise indicated, all variables are as defined above.

General Procedures

Compounds of Formula I of the present disclosure can be prepared asdepicted in Scheme 1.

Scheme 1 describes a method for preparation ofisoquinoline-3-carboxamide derivatives (IX) by first coupling the aminewith a variety of acids (III) to produce amide IV. The bromo derivativeIV is then reacted with bis(pinacolato)diboron to give the pinacol ester(V). Suzuki coupling with a variety of 5-membered heteroaryl bromides(VIII) yields the desired R³ substituted isoquinoline IX. Alternatively,the bromo derivative IV is Suzuki coupled with a variety of 5-memberedheteroaryl pinacol esters (VI) or coupled to a variety of 5-memberedheteroaryl stannanes (VII) to produce the final R³ substitutedisoquinoline IX.

In some embodiments, compounds of Formula I of the present disclosurecan be prepared as depicted in Scheme 2.

Scheme 2 describes a method for preparation ofisoquinoline-3-carboxamide intermediate (IVa) by first coupling theamine 4-nitrophenyl carbonochloridate followed by coupling with avariety of R⁶NH heterocyclyls. Intermediate IVa could then be used inplace of IV in Scheme 1 or 3.

In some embodiments, compounds of Formula I of the present disclosurecan be prepared as depicted in Scheme 3.

Scheme 3 describes a method for preparation ofisoquinoline-3-carboxamide derivatives (IXa) by first reacting withbis(pinacolato)diboron to give the pinacol ester (X). Suzuki couplingwith a variety of 5-membered heteroaryl bromides (VIII) yields thedesired R³ substituted isoquinoline amine XI. The amine (XI) is thenreacted with diphosgene to form the isocyanate (XII) which is thenreacted with a variety of a variety of R⁶NH heterocyclyls produce thefinal R³ and R⁶ substituted isoquinoline IXa.

In other embodiments, compounds of Formula I of the present disclosurecan be prepared as depicted in Scheme 4.

Scheme 4 describes a method for preparation ofisoquinoline-3-carboxamide derivatives (IXa) starting with bromointermediate IV or IVa and couple with the nitrogen of a variety of R³NHheteroaryls to produce the final R³ substituted isoquinoline IXa.

Illustrative Compound Examples

Preparation of intermediate 6-bromoisoquinolin-1-d-3-amine (XIV) isdepicted below in Scheme 5.

Step 1

To a mixture of 1,6-dibromoisoquinolin-3-amine (XIII) (0.5 g, 1.66mmol), ammonium formate-d₅ (0.56 g, 8.28 mmol) and Pd(PPh₃)₄ (191.3 mg,0.170 mmol) in DMF (5 mL) was heated to 50° C. for 48 h. The solventswere concentrated and the residue was suspended in chloroform. The solidwas collected by filtration and washed with water and EtOAc. The solidwere dried under high vacuo to obtain6-bromo-1-deuterio-isoquinolin-3-amine (XIV) (115 mg, 0.513 mmol, 31.0%yield) as a pale yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 6.11 (2H,s), 6.55 (1H, s), 7.22 (1H, dd, J=8.78, 1.92 Hz), 7.73 (1H, d, J=8.51Hz), 7.79 (1H, d, J=1.92 Hz); ESIMS found for C₉H₆DBrN₂ m/z 224.0(⁷⁹BrM+H).

Preparation of intermediate 6-bromo-4-chloroisoquinolin-3-amine (XVI) isdepicted below in Scheme 6.

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XV) (1.0 g, 4.48mmol) in DMF (15 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione(598.6 mg, 4.48 mmol) portionwise. The mixture was stirred at 0° C. for6 h. The reaction mixture was added to water (150 mL), stirred for 1 hand the resulting solids were collected by filtration and air driedovernight to obtain 6-bromo-4-chloro-isoquinolin-3-amine (XVI) (922 mg,3.58 mmol, 79.9% yield) as a beige solid which was used for next stepwithout purification. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.55 (2H, s), 7.40(1H, dd, J=8.64, 1.78 Hz), 7.88 (1H, d, J=8.51 Hz), 7.90 (1H, d, J=1.10Hz), 8.86 (1H, s); ESIMS found for C₉H₆BrClN₂ m/z 256.9 (⁷⁹BrM+H).

Preparation of intermediate 6-bromo-4-methylisoquinolin-3-amine (XVIII)is depicted below in Scheme 7.

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XV) (2.0 g, 8.97mmol) in DMF (25.1 mL) at 0° C. was added 1-iodopyrrolidine-2,5-dione(2.02 g, 8.97 mmol) portionwise, The mixture was stirred at 0° C. for 1hr. LC-MS of the mixture showed completion of the reaction and thedesired product. The solvent was removed under vacuum, the residue waspurified by C18 Silica gel (240 g) [0-→100% H₂O/MeCN (0.1% Formic acid)]to produce 6-bromo-4-iodo-isoquinolin-3-amine (XVII) (1.95 g, 5.58 mmol,62.2% yield) as a brown solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.41 (2H,br s), 7.40 (1H, dd, J=8.64, 1.78 Hz), 7.76-7.81 (1H, m), 7.82 (1H, d,J=8.51 Hz), 8.81 (1H, s); ESIMS found for C₉H₆BrIN₂ m/z 348.9 (⁷⁹BrM+H).

Step 2

A stirred solution of 6-bromo-4-iodo-isoquinolin-3-amine (XVII) (1.0 g,2.87 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.72 g, 2.87mmol), Pd(dppf)Cl₂ (0.23 g, 0.29 mmol), and K₃PO₄ (5.73 mL, 5.73 mmol)in 1,4-dioxane (10 mL) was heated to 90° C. for 3 days. The solvent wasremoved under high vacuum and the residue was purified by C18 silica gel(240 g) [0-20% H₂O/MeCN (0.1% Formic acid)] to produce6-bromo-4-methyl-isoquinolin-3-amine (XVIII) (74 mg, 0.312 mmol, 10.9%yield) as an off-white solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.23 (3H,br s), 5.91 (2H, br s), 7.27 (1H, br d, J=2.20 Hz), 7.71-7.82 (1H, m),7.92 (1H, br s), 8.72 (1H, br s); ESIMS found for C₁₀H₉BrN₂ m/z 239.0(⁸¹BrM+H).

Preparation of intermediate 6-bromo-7-fluoroisoquinolin-3-amine (XXI) isdepicted below in Scheme 8.

Step 1

To a vial was added 2,2-diethoxyacetonitrile (XIX) (1.0 g, 7.74 mmol)dissolved MeOH (7.74 mL) followed by addition of MeONa/MeOH (0.18 mL,0.77 mmol) dropwise. The reaction was stirred at room temperature for 20h. HOAc (44.3 μL, 0.77 mmol) was added until pH=7-8 (using pH strips).(4-Bromo-3-fluoro-phenyl)methanamine hydrochloride (XX) (1.86 g, 7.74mmol) was added and stirred at 40° C. for 4 h. The solvent was removedunder vacuum. Sulfuric acid (12.6 mL, 232.3 mmol) was added and stirredat 40° C. for 16 h. NH₄OH (30.8 mL, 240.0 mmol) was added dropwise at 0°C. The solvent was removed under vacuum and the residue was purified byC18 silica gel (240 g) [0-50% H₂O/MeCN (0.1% Formic acid)] to produce6-bromo-7-fluoro-isoquinolin-3-amine (XXI) (1.33 g, 5.50 mmol, 71.1%yield) as an off-white solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.07 (2H,s), 6.61 (1H, s), 7.76 (1H, d, J=9.33 Hz), 8.01 (1H, d, J=6.86 Hz), 8.80(1H, s); ESIMS found for C₉H₆BrFN₂ m/z 242.9 (⁸¹BrM+H).

Preparation of intermediates 6-bromo-7-chloroisoquinolin-3-amine (XXIII)and 6-bromo-5-chloroisoquinolin-3-amine (XXIV) is depicted below inScheme 9.

Step 1

To a stirred solution of 2,2-diethoxyacetonitrile (XIX) (0.59 g, 4.57mmol) in a vial containing MeOH (4.57 mL) was added MeONa (0.1 mL, 0.46mmol) dropwise. The reaction was stirred at 35° C. for 20 h. HOAc wasadded (26.1 μL, 0.46 mmol) (checked that the pH is 7-8 using pH strips)followed by (4-bromo-3-chloro-phenyl)methanamine (XXII) (1.01 g, 4.57mmol). The mixture was stirred at 35° C. for 40 h. The solvent wasremoved under vacuum. Sulfuric Acid (7.43 mL, 137.0 mmol) was then addedand stirred at 35° C. for 16 h. NH₄OH (60.6 mL, 141.6 mmol) was added at0° C. The reaction was filtered through Celite and purified by C18silica gel (240 g) [0→30% H₂O/MeCN (0.1% Formic acid)] to produce a 1:1mixture (by NMR) of 6-bromo-7-chloro-isoquinolin-3-amine (XXIII) and6-bromo-5-chloroisoquinolin-3-amine (XXIV) (633.7 mg, 2.46 mmol, 53.9%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.23 (2H, s), 6.46 (2H, s), 6.57(1H, s), 6.83 (1H, s), 7.40 (1H, d, J=8.51 Hz), 7.74 (1H, d, J=8.51 Hz),8.05 (1H, s), 8.09 (1H, s), 8.81 (1H, s), 8.88 (1H, s); ESIMS found forC₉H₆BrClN₂ m/z 256.9 (⁷⁹BrM+H).

Preparation of intermediates 6-bromo-7-methylisoquinolin-3-amine (XXVI)and 6-bromo-5-methylisoquinolin-3-amine (XXVII) is depicted below inScheme 10.

Step 1

To a stirred solution of 2,2-diethoxyacetonitrile (XIX) (0.33 g, 2.52mmol) in a vial containing MeOH (2.52 mL) was added MeONa (0.23 mL, 0.25mmol) dropwise. The reaction was stirred at 22° C. for 20 h. HOAc wasadded (14.4 μL, 0.25 mmol) (checked that the pH is 7-8 using pH strips)followed by (4-bromo-3-methyl-phenyl)methanamine (XXV) (0.5 g, 2.52mmol). The mixture was stirred at 40° C. for 40 h. The solvent wasremoved under vacuum. Sulfuric Acid (4.09 mL, 75.49 mmol) was then addedand stirred at 40° C. for 16 h. NH₄OH (33.4 mL, 78 mmol) was added at 0°C. The reaction was filtered through Celite and purified by C18 silicagel (240 g) [0→30% H₂O/MeCN (0.1% Formic acid)] to produce a 1:1 mixture(by NMR) of 6-bromo-7-methylisoquinolin-3-amine (XXVI) and6-bromo-5-methylisoquinolin-3-amine (XXVII) (378 mg, 1.59 mmol, 63.4%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.40 (3H, s), 2.52 (3H, s), 5.96(2H, s), 6.12 (1H, s), 6.54 (1H, s), 6.71 (1H, s), 7.27 (1H, d, J=8.78Hz), 7.58 (1H, d, J=8.78 Hz), 7.73 (1H, s), 7.86 (1H, s), 8.74 (1H, s),8.79 (1H, s); ESIMS found for C₁₀H₉BrN₂ m/z 237.0 (⁷⁹BrM+H).

Preparation of intermediate trans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexane-1-carboxylic acid (XXX) is depicted below in Scheme 11.

Step 1

To a solution of methyltrans-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylate (XXVIII)(1.3 g, 5 mmol) in DMF (15 mL) and cooled to 0° C. was added sodiumhydride (60% in oil, 240 mg, 6 mmol) over 30 minutes. The mixture isstirred at room temperature for 1 h, then cooled to 0° C. and treatedwith iodomethane (0.38 mL, 6 mmol). After stirring overnight at roomtemperature, the mixture is poured into a saturated aqueous ammoniumchloride and extracted with EtOAc. The combined organic phase is washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The obtained residue is purified by columnchromatography on silica gel (eluent: n-hexane-EtOAc 10:1) to obtainmethyltrans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexane-1-carboxylate(XXIX) (1.3 g, 4.79 mmol, 94.8% yield).

Step 2

To a stirred solution of methyltrans-4-((tert-butoxycarbonyl)(methyl)amino) cyclohexane-1-carboxylate(XXIX) (130 mg, 4.79 mmol) in a mixture of MeOH (10 mL) and THF (10 mL)was added 2 N aqueous NaOH (4.79 mL, 9.58 mmol) and the mixture wasstirred for 4 h. The solvent was concentrated, the residue taken inwater and acidified with 1N HCl and extracted with EtOAc. The organicswere washed with 2× water then 1× brine. The organics were thenseparated and dried (MgSO₄) before concentration to dryness to obtaintrans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexane-1-carboxylicacid (XXX) as a thick gum (1.198 g, 4.65 mmol, 97.2% yield) which wasused for next step without purification.

Preparation of intermediate 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)isonicotinic acid (XXXIV) is depicted below in Scheme 12.

Step 1

To a solution of ethyl 2-chloroisonicotinate (XXXI) (10 g, 53.88 mmol)was added tert-butyl piperazine-1-carboxylate (XXXII) (0.32 mL, 2.89mmol) and DIPEA (18.8 mL, 107.75 mmol). The reaction was stirred at 110°C. for 16 h. The mixture was poured into water, extracted with EtOAc,and dried over Na₂SO₄. The solvent was removed under high vacuum and theresidue was purified on a silica gel column (120 g) (0-100%hexane/EtOAc) to give tert-butyl4-(4-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (XXXIII) as abrown oil (10.84 g, 32.32 mmol, 60.0% yield). ESIMS found for C₁₇H₂₅N₃O₄m/z 336.15 (M+H).

Step 2

To a solution of tert-butyl4-(4-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (XXXIII)(10.7 g, 31.9 mmol) in MeOH (130 mL) and water (26 mL) was added 4 Maqueous lithium hydroxide (7.98 mL, 31.9 mmol). The reaction was stirredat room temperature for 16 h. The reaction was poured into water andneutralized with concentrated hydrogen chloride (31.9 mL, 31.9 mmol) andextracted with EtOAc, The organic layer was dried over Na₂SO₄ andevaporated under high vacuum to produce2-(4-(tert-butoxycarbonyl)piperazin-1-yl)isonicotinic acid (XXXIV) as awhite solid (8.79 g, 28.6 mmol, 89.7% yield) which was used withoutfurther purification. ESIMS found for C₁₅H₂₁N₃O₄ m/z 308.15 (M+H).

Example 1

Preparation oftrans-N-(8-fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide(19) is depicted below in Scheme 13.

Step 1

To a stirred solution of 6-bromo-8-fluoroisoquinolin-3-amine (XXXV)(AbovChem-AC614182) (1.0 g, 4.15 mmol), DIPEA (1.81 mL, 10.37 mmol),HATU (1.97 g, 5.19 mmol) and DMAP (50.7 mg, 0.41 mmol) in DMF (16 mL)was added trans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexane-1-carboxylic acid (XXXVI) (1.26 g, 5.19 mmol). The mixturewas heated to 70° C. overnight. An additional 0.5 equiv. of HATU wasadded and the mixture was stirred for another 5 h at 70° C. (repeatedtwice). The reaction mixture was poured into a saturated aqueous NaHCO₃solution (˜200 mL) and stirred for 20 min. The resulting solids werecollected by filtration, washed with water and dried under high vacuo toobtain tert-butyltrans-4-((6-bromo-8-fluoroisoquinolin-3-yl)carbamoyl)cyclohexyl)carbamate(XXXVII) as a beige color solid (1.54 g, 3.30 mmol, 79.6% yield) whichwas used for next step without purification. ESIMS found forC₂₁H₂₅BrFN₃O₃ m/z 466.1 (⁷⁹BrM+H).

Step 2

To a stirred solution of tert-butyltrans-4-((6-bromo-8-fluoroisoquinolin-3-yl)carbamoyl)cyclohexyl)carbamate (XXXVII) (1.54 g, 3.3 mmol) in DCM (10mL) was added TFA (6. mL, 77.9 mmol) and the mixture was stirred for 1h. The reaction mixture was concentrated, treated with 7 N NH₃/MeOH,absorbed on silica gel and was purified by column chromatography(20→100% CHCl₃/10%7N NH₃/MeOH in CHCl₃). The pure fractions werecombined and concentrated. The residue was suspended in EtOAc, sonicatedand filtered. The solid was dried under high vacuo to obtaintrans-4-amino-N-(6-bromo-8-fluoroisoquinolin-3-yl)cyclohexane-1-carboxamide(XXXVIII) as an off-white color solid (644 mg, 1.76 mmol, 53.2% yield).ESIMS found for C₁₆H₁₇BrFN₃O m/z 366.1 (⁷⁹BrM+H).

Step 3

A stirred suspension oftrans-4-amino-N-(6-bromo-8-fluoroisoquinolin-3-yl)cyclohexane-1-carboxamide (XXXVIII) (380 mg, 1.04 mmol),1-bromo-2-(2-bromoethoxy)ethane (XXXIX) (0.16 mL, 1.25 mmol) and K₂CO₃(430.2 mg, 3.11 mmol) in MeCN (5 mL) was heated to reflux for 24 h. Thereaction mixture was concentrated and the residue was taken into DCM,washed with water and brine. The organics were then separated and dried(MgSO₄) before concentration to dryness. The crude was purified bycolumn chromatography (0→30% CHCl₃/10% 7N NH₃MeOH in CHCl₃). The purefractions were combined, concentrated and dried to obtain the desiredproducttrans-N-(6-bromo-8-fluoroisoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide(XL) as an off-white solid (205 mg, 0.47 mmol, 45.3% yield). ESIMS foundfor C₂₀H₂₃BrFN₃O₂ m/z 436.1 (⁷⁹BrM+H).

Step 4

To a solution oftrans-N-(6-bromo-8-fluoroisoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide(XL) (100 mg, 0.23 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (XLI)(60 mg, 0.29 mmol), K₂CO₃ (0.29 mL, 0.57 mmol) in MeCN (1 mL) was addedPd(dppf)Cl₂ (18.7 mg, 0.02 mmol). N₂ gas was bubbled into the mixturefor 10 min and then heated to 110° C. for 30 min using microwave (MW)irradiation. The organic layer was carefully separated, absorbed onsilica gel and purified by column chromatography (0-60% CHCl₃/10% 7NNH₃MeOH in CHCl₃). The pure fractions were combined, concentrated andthe product was suspended in EtOAc, sonicated and the solids werecollected by filtration, washed with diethyl ether and dried under highvacuo to obtaintrans-N-(8-fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide19 as a white solid (30.0 mg, 0.068 mmol, 29.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.15-1.28 (2H, m), 1.42-1.54 (2H, m), 1.92 (4H, br t,J=12.76 Hz), 2.15-2.28 (1H, m), 2.46-2.49 (4H, m), 2.53 (3H, s),3.52-3.60 (4H, m), 7.65 (1H, dd, J=11.53, 1.10 Hz), 7.84 (1H, s), 7.95(1H, s), 8.56 (1H, s), 9.22 (1H, s), 10.66 (1H, s) ESIMS found forC₂₄H₂₇FN₄O₃ m/z 439.2 (M+1).

Example 2

Preparation oftrans-4-(dimethylamino)-N-(8-fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide (17) is depicted below inScheme 14.

Step 1

To a solution of trans-4-amino-N-(6-bromo-8-fluoroisoquinolin-3-yl)cyclohexane-1-carboxamide (XXXVIII) (644 mg, 1.76 mmol) in MeOH (50 mL)was added formaldehyde (1.76 mL, 8.76 mmol). After 15 min, Na(OAc)₃BH(1.86 g, 8.76 mmol) was added and the mixture was stirred at roomtemperature 2 h. The solvents were removed in vacuo, the residue waspartitioned between CHCl₃/1N aqueous NaOH. The organic layer wasseparated, washed with water and brine, dried over anhydrous Na₂SO₄ andthe solvents were concentrated to obtaintrans-N-(6-bromo-8-fluoro-3-isoquinolyl)-4-(dimethylamino)cyclohexanecarboxamide(XLII) as an off-white color solids (295 mg, 0.75 mmol, 42.5% yield)which was used for next step without purification. ESIMS found forC₁₈H₂₁BrFN₃O m/z 394.1 (⁷⁹BrM+H).

Step 2

To a solution oftrans-N-(6-bromo-8-fluoro-3-isoquinolyl)-4-(dimethylamino)cyclohexanecarboxamide (XLII) (200 mg, 0.51 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (XLI)(133 mg, 0.63 mmol), and K₂CO₃ (0.63 mL, 1.27 mmol) in MeCN (2.5 mL) wasadded Pd(dppf)Cl₂ (41.4 mg, 0.05 mmol). N₂ gas was bubbled into themixture for 10 min and then heated to 110° C. for 30 min using microwave(MW) irradiation. The organic layer was carefully separated, absorbed onsilica gel and purified by column chromatography (0→60% CHCl₃/10% 7NNH₃MeOH in CHCl₃). The pure fractions were combined, concentrated andthe product was suspended in EtOAc, sonicated and the solids werecollected by filtration, washed with diethyl ether and dried under highvacuo to obtaintrans-4-(dimethylamino)-N-(8-fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 17 as a beige solid (115.0 mg, 0.290 mmol,57.2% yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.13-1.25 (2H, m), 1.47(2H, qd, J=12.76, 2.61 Hz), 1.83-1.90 (2H, m), 1.90-1.96 (2H, m),2.09-2.22 (1H, m), 2.18 (6H, s), 2.45-2.49 (1H, m), 2.53 (3H, s), 7.64(1H, dd, J=11.39, 0.96 Hz), 7.83 (1H, s), 7.95 (1H, s), 8.56 (1H, s),9.22 (1H, s), 10.65 (1H, s); ESIMS found for C₂₂H₂₅FN₄O₂ m/z 397.2(M+1).

Example 3

Preparation of N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide (5) and1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide(6) is depicted below in Scheme 15.

Step 1

A mixture of ammonium formate-d₅ (972.3 mg, 14.28 mmol), 10% Pd—C(50%w/w in water) (200 mg, 2.86 mmol) and4-iodo-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine(XLIII)(synthesized using the procedure shown in scheme 13, step 4)(1.0g, 2.86 mmol) in DMF (15 mL) was heated to 50° C. for 16 h. The reactionmixture was cooled, filtered through Celite, washed with water, thenEtOH, and dried under high vacuo to obtain6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-4-d-3-amine (XLIV) as a palegreen color solid (506 mg, 2.25 mmol, 78.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 4.12 (3H, s), 5.94 (2H, s), 6.65 (1H, s), 7.61 (1H, dd,J=8.51, 1.65 Hz), 7.85 (1H, d, J=8.51 Hz), 7.96 (1H, s), 8.64 (1H, s),8.79 (1H, s); ESIMS found for C₁₃H₁₁DN₄ m/z 226.1 (M+1).

Step 2

A mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (XLV)(190.8 mg, 0.83 mmol), DIPEA (0.58 mL, 3.33 mmol) and HATU (316.5 mg,0.83 mmol), 6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-4-d-3-amine (XLIV)(150 mg, 0.67 mmol) and DMAP (8.13 mg, 0.07 mmol) in DMF (2 mL) washeated to 70° C. overnight. An additional 0.5 equiv. of HATU was addedand the mixture was stirred for another 5 h at 70° C. (repeated twice).The reaction mixture was poured into a saturated aqueous NaHCO₃ solution(˜100 mL), extracted with EtOAc, washed with water, brine and dried overanhydrous Na₂SO₄. The organic layer was concentrated and dried underhigh vacuo to obtain tert-butyl4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)carbamoyl)piperidine-1-carboxylate(XLVI) as a beige color solid (336 mg, 0.77 mmol, 115.6% yield) whichwas used for next step without purification. ESIMS found for C₂₄H₂₈DN₅O₃m/z 437.2 (M+1).

Step 3

To a solution of tert-butyl4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)carbamoyl)piperidine-1-carboxylate(XLVI) (290.7 mg, 0.67 mmol) in DCM (2 mL) was added TFA (76 mg, 0.67mmol) and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated, treated with 7 N NH₃/MeOH, absorbedon silica gel and purified by column chromatography (20→100% CHCl₃/10%7N NH₃MeOH in CHCl₃). The pure fractions were combined, concentrated anddried under high vacuo to obtainN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide5 as an off-white color solid (130 mg, 0.39 mmol, 58.0% yield). ¹H NMR(499 MHz, DMSO-d₆) δ ppm 1.53 (2H, qd, J=12.21, 3.98 Hz), 1.67-1.74 (2H,m), 2.13 (1H, br s), 2.43-2.49 (2H, m), 2.59-2.69 (1H, m), 2.94-3.01(2H, m), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d,J=8.51 Hz), 8.03 (1H, s), 8.08 (1H, s), 8.35 (1H, s), 9.02 (1H, s),10.40 (1H, s); ESIMS found for C₁₉H₂₀DN₅O m/z 337.2 (M+1).

Step 4

To a solution ofN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide5 (60 mg, 0.18 mmol) in MeOH (2 mL) was added 2-methylpropanal (0.02 mL,0.27 mmol) and the mixture was stirred for 15 min. NaCNBH₃ (16.8 mg,0.27 mmol) was then added and the mixture was stirred for 16 h. Thesolvent was concentrated and the residue taken into chloroform andwashed with brine. The organic layer was then separated, dried (MgSO₄)and concentrated to dryness. The crude product was then purified bypreparative TLC (50% CHCl₃/10% 7N NH₃MeOH in CHCl₃) to obtain1-isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide6 as a white solid (35.0 mg, 0.089 mmol, 50.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.73-1.81(3H, m), 1.82-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.57 (1H, m),2.86 (2H, br d, J=11.53 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.64, 1.51Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s),9.02 (1H, s), 10.45 (1H, s); ESIMS found for C₂₃H₂₈[²H]N₅O m/z 393.25(M+1).

Example 4

Preparation of trans-4-(hydroxymethyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide (43) andtrans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-(morpholinomethyl)cyclohexane-1-carboxamide (69) aredepicted below in Scheme 16.

Step 1

To a mixture of 6-bromoisoquinolin-3-amine (XV) (1.0 g, 4.48 mmol)2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (XLI)(1.17 g, 5.6 mmol) Pd(dppf)Cl₂ (0.66 g, 0.81 mmol) in dioxane (20 mL)was added K₃PO₄ (56.0 mL, 112.07 mmol). N₂ gas was bubbled into thereaction mixture for 15 min and then heated to 90° C. for 16 h. Thereaction mixture was poured into a mixture of DCM (30 mL) and water (30mL) and adjusted the pH to 1-2 with concentrated HCl. The suspension wasfiltered and the aqueous layer was separated and adjusted the pH to 12with adding 10 N aqueous NaOH solution. The resulting solid wascollected by filtration, washed with water and dried under high vacuo at60° C. for 24 h to obtain 6-(2-methyloxazol-5-yl)isoquinolin-3-amine(XLVII) as a yellow color solid (0.844 g, 3.75 mmol, 83.6% yield). ¹HNMR (499 MHz, DMSO-d₆) δ ppm 2.53 (3H, s), 5.99 (2H, br s), 6.64 (1H, brs), 7.35-7.50 (1H, m), 7.67 (1H, br s), 7.75 (1H, br s), 7.80-7.91 (1H,m), 8.78 (1H, br s); ESIMS found for C₁₃H₁₁N₃O m/z 226.1 (M+1).

Step 2

A mixture of 6-(2-methyloxazol-5-yl)isoquinolin-3-amine (XLVII) (0.5 g,2.22 mmol), HATU (1.06 g, 2.77 mmol),trans-4-(((tert-butyldimethylsilyl)oxy)methyl) cyclohexane-1-carboxylicacid (XLVIII) (0.76 g, 2.77 mmol), DIPEA (1.16 mL, 6.66 mmol) and DMAP(0.05 g, 0.44 mmol) in DMF (6 mL) was heated to 80° C. overnight. Themixture was added to aqueous saturated NaHCO₃ and extracted with EtOAc.The organic layer was washed with water and then brine. The organiclayer was separated and dried (MgSO₄) before concentration to drynessunder high vacuum. The crude product was then purified by ISCO (10-70%EtOAc/hexanes) to obtaintrans-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide(XLIX) as a white color solid (970 mg, 2.02 mmol, 91.1% yield). ESIMSfound for C₂₇H₃₇N₃O₃Si m/z 480.25 (M+1).

Step 3

To a solution oftrans-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide(XLIX) (950 mg, 1.98 mmol) in THF (8 mL) was added 1 M solution of TBAF(2.97 mL, 2.97 mmol) and the mixture was stirred at 25° C. for 16 h. Thereaction mixture was absorbed on silica gel and was purified bychromatography (0→5% CHCl₃/MeOH) to obtaintrans-4-(hydroxymethyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide43 as a white solid (355.0 mg, 0.972 mmol, 49.1% yield). ¹H NMR (500MHz, DMSO-d₆) δ ppm 0.95 (2H, qd, J=12.76, 2.88 Hz), 1.31-1.40 (1H, m),1.45 (2H, qd, J=12.67, 3.43 Hz), 1.80 (2H, br dd, J=13.17, 2.47 Hz),1.88 (2H, br dd, J=13.04, 2.61 Hz), 2.42-2.48 (1H, m), 2.53 (3H, s),3.24 (2H, t, J=5.76 Hz), 4.39 (1H, t, J=5.35 Hz), 7.79 (1H, s),7.79-7.84 (1H, m), 8.09 (1H, s), 8.10 (1H, d, J=6.04 Hz), 8.50 (1H, s),9.10 (1H, s), 10.49 (1H, s); ESIMS found for C₂₁H₂₃N₃O₃ m/z 366.2 (M+1).

Step 4

To a solution of DMSO (0.2 mL, 2.87 mmol) in DCM (3 mL) at −78° C. wasadded under Argon dropwise oxalyl chloride (0.13 mL, 1.44 mmol) in DCM(1 mL). After 15 min,trans-4-(hydroxymethyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide43 (350 mg, 0.96 mmol) in DCM (3 mL) was added and the mixture wasstirred at -78° C. for 1 h. TEA (0.4 mL, 2.87 mmol) was then added andthe mixture was continued to stir for 1 h and then warmed to roomtemperature for 1 h. The reaction mixture was diluted with H₂O and DCM,organic layer separated, washed with brine, dried over anhydrous Na₂SO₄and the solvents were concentrated in vacuo to obtaintrans-4-formyl-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide(L) as a pale yellow color solid (215.0 mg, 0.59 mmol, 108.1% yield)which was used for next step without purification. ESIMS found forC₂₁H₂₁N₃O₃ m/z 364.2 (M+1).

Step 5

To a solution oftrans-4-formyl-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide (L) (100 mg, 0.28 mmol) in a mixture of MeOH(0.50 mL) and DCE (1 mL) was added morpholine hydrochloride (68 mg, 0.55mmol)(pre-treated with TEA (0.08 mL, 0.55 mmol)). The mixture wasstirred for 10 min before adding Na(OAc)₃BH (116.6 mg, 0.55 mmol) andstirring for another 4 h. The reaction mixture was diluted with DCM,washed with aqueous saturated NaHCO₃ and brine. The organic layer wasseparated and dried over anhydrous Na₂SO₄. The solvent evaporated underhigh vacuum and the crude product was then purified by preparative TLC(50% CHCl₃/10% 7N NH₃MeOH in CHCl₃) to obtaintrans-N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-4-(morpholinomethyl)cyclohexane-1-carboxamide 69 an off-white solid (21.0 mg, 0.048 mmol,17.6% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.81-0.94 (2H, m),1.41-1.56 (3H, m), 1.80-1.91 (4H, m), 2.09 (2H, d, J=7.41 Hz), 2.31 (4H,br s), 2.51-2.56 (1H, m), 2.53 (3H, s), 3.56 (4H, t, J=4.53 Hz), 7.78(1H, s), 7.79-7.84 (1H, m), 8.05-8.11 (2H, m), 8.50 (1H, s), 9.10 (1H,s), 10.49 (1H, s); ESIMS found for C₂₅H₃₀N₄O₃ m/z 435.2 (M+1).

Example 5

Preparation of trans-4-(methylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl) cyclohexane-1-carboxamide (16) andtrans-4-(methyl(oxetan-3-yl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide(37) are depicted below in Scheme 17.

Step 1

A mixture of DIPEA (2.93 mL, 16.81 mmol), HATU (1.6 g, 4.2 mmol) DMAP(41 mg, 0.34 mmol),trans-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexane--carboxylic acid(XXX) (1.2 g, 4.66 mmol) and 6-bromoisoquinolin-3-amine (XV) (750 mg,3.36 mmol) in DMF (8 mL) was heated to 80° C. overnight. An additional0.25 equiv. of HATU was added and the mixture was stirred for another 5h at 80° C. The reaction mixture was poured into aqueous saturatedNaHCO₃ solution (˜200 mL), stirred for 20 min, the resulting solid wascollected by filtration, washed with water and concentrated under highvacuum. The crude product was purified by column chromatography (0 to40% EtOAc/hexanes). The pure fractions were combined, concentrated anddried under high vacuo to obtain tert-butyl(trans-4-((6-bromoisoquinolin-3-yl)carbamoyl)cyclohexyl)(methyl)carbamate(LI) as a beige color solid (0.513 g, 1.11 mmol, 33.0% yield). ESIMSfound for C₂₂H₂₈BrN₃O₃ m/z 462.1 (⁷⁹BrM+1).

Step 2

A mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (XLI) (283 mg, 1.35 mmol), Pd(dppf)Cl₂ (88.3 mg, 0.11 mmol), 2Maqueous K₂CO₃ (1.35 mL, 2.7 mmol) and tert-butyl(trans-4-((6-bromoisoquinolin-3-yl)carbamoyl)cyclohexyl)(methyl)carbamate (LI) (500 mg, 1.08 mmol) in MeCN (5 mL). N₂gas was bubbled into the mixture for 10 min and then was heated to 95°C. for 16 h. The organic layer was carefully separated, absorbed onsilica gel and purified by column chromatography (25-100%hexanes/EtOAc). The pure fractions were combined, concentrated and driedunder high vacuo to obtain tert-butylmethyl(trans-4-((6-(2-methyloxazol-5-yl)isoquinolin-3-yl)carbamoyl)cyclohexyl)carbamate (LII) as an off-white color solid (228 mg, 0.49mmol, 45.4% yield). ESIMS found for C₂₆H₃₂N₄O₄ m/z 465.3 (M+1).

Step 3

To a stirred solution of TFA (1.3 g, 11.42 mmol) in DCM (1 mL) was addedtert-butylmethyl(trans-4-((6-(2-methyloxazol-5-yl)isoquinolin-3-yl)carbamoyl)cyclohexyl)carbamate (LII) (225 mg, 0.48 mmol) and the mixture was stirred for 1 h.The reaction mixture was concentrated, treated with 7 N NH₃/MeOH,absorbed on silica gel and purified by column chromatography (20-100%CHCl₃/10% 7N NH₃MeOH in CHCl₃). The pure fractions were combined,concentrated and dried under high vacuo to obtaintrans-4-(methylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide16 as an off-white solid (131.0 mg, 0.360 mmol, 74.2% yield). ¹H NMR(499 MHz, DMSO-d₆) δ ppm 0.93-1.04 (2H, m), 1.48 (2H, qd, J=12.85, 3.16Hz), 1.86 (2H, br d, J=11.25 Hz), 1.95 (2H, br dd, J=13.17, 3.02 Hz),2.22 (1H, tt, J=10.94, 4.01 Hz), 2.28 (3H, s), 2.53 (3H, s), 7.78 (1H,s), 7.79-7.84 (1H, m), 8.06-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s),10.49 (1H, s); ESIMS found for C₂₁H₂₄N₄O₂ m/z 365.2 (M+1).

Step 4

To a stirred solution of Na(OAc)₃BH (52.3 mg, 0.25 mmol) andoxetan-3-one (LIII) (17.8 mg, 0.25 mmol) in a mixture of MeOH (0.50 mL)and DCE (1 mL) was addedtrans-4-(methylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide16 (60 mg, 0.16 mmol) and the mixture was stirred for 72 h. The reactionmixture was absorbed on silica gel and purified by preparative TLC (60%CHCl₃/10% 7N NH₃MeOH in CHCl₃) to obtaintrans-4-(Methyl(oxetan-3-yl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide37 as a white solid (6.0 mg, 0.014 mmol, 8.7% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.16-1.30 (2H, m), 1.47 (2H, qd, J=12.72, 2.74 Hz), 1.68(2H, br d, J=10.15 Hz), 1.85-1.94 (2H, m), 2.12 (3H, s), 2.30 (1H, tt,J=11.53, 3.02 Hz), 2.41-2.48 (1H, m), 2.53 (3H, s), 3.90 (1H, quin,J=6.86 Hz), 4.43-4.53 (4H, m), 7.78 (1H, s), 7.80 (1H, dd, J=8.64, 1.51Hz), 8.05-8.12 (2H, m), 8.49 (1H, s), 9.10 (1H, s), 10.50 (1H, s); ESIMSfound for C₂₄H₂₈N₄O₃ m/z 421.2 (M+1).

Example 6

Preparation of N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide (24),1-(2,2-difluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide (27) and1-(2,2-difluoropropyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide(28) are depicted below in Scheme 18.

Step 1-2

To a mixture of 6-bromoisoquinolin-3-amine (XV) (4.52 g, 20.27 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (LIV) (5.62g, 22.12 mmol), KOAc (5.43 g, 55.29 mmol), and Pd(dppf)Cl₂ (3.0 g, 3.69mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 90°C. for 2 h. The reaction was cooled to room temperature before addingthe 2-bromo-5-methyl-1,3,4-thiadiazole (LV) (3.30 g, 18.43 mmol), K₂CO₃(7.64 g, 55.29 mmol) and Pd(dppf)Cl₂ (3.0 g, 3.69 mmol). The mixture washeated at 90° C. for another 4 h. The solvent was removed under highvacuum and the residue was purified by column chromatography (0→100%EtOAc/hexanes) to produce6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-amine (LVI) as a yellowsolid (4.30 g, 17.75 mmol, 96.3% yield). ESIMS found for C₁₂H₁₀N₄S m/z243.0 (M+1).

Step 3

To a suspension of 6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-amine(LVII) (0.4 g, 1.65 mmol),1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (XLV) (0.45 g, 1.98mmol), DMAP (0.1 g, 0.83 mmol) and HATU (0.75 g, 1.98 mmol) in MeCN (4mL) was added DIPEA (0.86 mL, 4.95 mmol). The resulting mixture washeated at 80° C. for 16 h. The reaction was concentrated under highvacuum and then purified via column chromatography (24 g of silica gel)(0→3% CHCl₃/10% 7N NH₃MeOH) to yield tert-butyl4-((6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate(LVII) as a light orange solid (590 mg, 1.30 mmol, 78.8% yield). ESIMSfound for C₂₃H₂₇N₅O₃S m/z 454.2 (M+1).

Step 4

A solution of tert-butyl4-((6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate(LVII (0.59 g, 1.3 mmol) in TFA (2.16 mL, 28.08 mmol) stirred at roomtemperature for 2 h. The reaction was concentrated under vacuum andneutralized with a NH₃ in CHCl₃ solution. The solution was concentratedand purified via column chromatography (12 g of silica gel) (0→1%CHCl₃/MeOH) to giveN-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide24 as a light green solid (105.0 mg, 0.297 mmol, 22.8% yield). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.93-2.02 (2H, m), 2.05-2.20 (5H, m), 2.22 (3H,s), 2.71-2.77 (2H, m), 2.83 (3H, s), 8.15 (1H, dd, J=8.64, 1.78 Hz),8.24 (1H, d, J=8.51 Hz), 8.52 (1H, s), 8.59 (1H, s), 9.27 (1H, s), 10.08(1H, d, J=4.12 Hz); ESIMS found for C₁₈H₁₉N₅OS m/z 354.1 (M+1).

Step 5

A solution of N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide 24 (50 mg, 0.14 mmol), K₂CO₃ (39.1 mg, 0.28mmol), KI (46.5 mg, 0.28 mmol) and 2,2-difluoropropyl4-methylbenzenesulfonate (LVIII) (70.8 mg, 0.28 mmol) in DMF (10 mL)heated at 160° C. overnight in a sealed vial. The reaction waspartitioned between EtOAc/water. The organic phase was separated and theaqueous phase was washed again with EtOAc. The organic phases werecombined, washed sequentially with water and brine, dried, andconcentrated. The residue was purified via column chromatography (12 gof silica gel) (0→3% CHCl₃/10% 7 N NH₃MeOH) to yield1-(2,2-difluoropropyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide28 as a beige solid (3.0 mg, 0.007 mmol, 4.9% yield). H NMR (500 MHz,DMSO-d₆) δ ppm 1.63 (3H, t, J=19.07 Hz), 1.67-1.75 (2H, m), 1.75-1.81(2H, m), 2.22 (2H, td, J=11.73, 2.33 Hz), 2.52-2.60 (1H, m), 2.71 (2H,t, J=14.00 Hz), 2.83 (3H, s), 2.92-2.99 (2H, m), 8.09 (1H, dd, J=8.51,1.65 Hz), 8.19 (1H, d, J=8.78 Hz), 8.45 (1H, d, J=0.82 Hz), 8.62 (1H,s), 9.21 (1H, s), 10.64 (1H, s); ESIMS found for C₂₁H₂₃F₂N₅OS m/z 432.2(M+1).

Step 6

To a suspension ofN-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide 24 (45 mg, 0.13 mmol) and K₂CO₃ (22.9 mg, 0.38mmol) in acetonitrile (20 mL) was added 1,1-difluoro-2-iodoethane (LIX)(29.3 mg, 0.15 mmol) and potassium iodide (41.5 mg, 0.25 mmol). Themixture was then heated to 80° C. overnight. The reaction mixture wasabsorbed on silica and was purified by ISCO (0→4% CHCl₃/10% 7 NNH₃MeOH). The pure fractions were combined, concentrated, suspended indiethyl ether, sonicated and the solids were collected by filtration anddried under high vacuo to obtain1-(2,2-difluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide27 as a beige solid (20.0 mg, 0.048 mmol, 53.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.74 (2H, m), 1.76-1.83 (2H, m), 2.14-2.25 (2H, m),2.52-2.61 (1H, m), 2.73 (2H, td, J=15.71, 4.25 Hz), 2.83 (3H, s), 2.96(2H, br d, J=11.53 Hz), 6.14 (1H, tt, J=56.10, 4.40 Hz), 8.09 (1H, dd,J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.45 (1H, s), 8.62 (1H, s),9.21 (1H, s), 10.64 (1H, s); ESIMS found for C₂₀H₂₁F₂N₅OS m/z 418.1(M+1).

Example 7

Preparation of1-methyl-3-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(1-methylpiperidin-4-yl)urea(29),(3S,4S)-4-amino-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide(33) and(3S,4S)-4-(dimethylamino)-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide(34) are depicted below in Scheme 19.

Step 1

To a stirred suspension of6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-amine (LVI) (400 mg,1.65 mmol), DMAP (20.2 mg, 0.17 mmol) and TEA (0.92 mL, 6.6 mmol) in THF(20 mL) was added diphosgene (0.2 mL, 1.65 mmol). The mixture wasstirred for 1 h at room temperature. LC-MS showed the formation of2-(3-isocyanatoisoquinolin-6-yl)-5-methyl-1,3,4-thiadiazole (LX) whichwas not isolated and was used immediately for the next step.

Step 2

To the 2-(3-isocyanatoisoquinolin-6-yl)-5-methyl-1,3,4-thiadiazole (LX)(1.65 mmol) reaction solution from the procedure in Step 1 was addedN,1-dimethylpiperidin-4-amine (LXI) (212 mg, 1.65 mmol) and the mixturewas stirred for 2 h at room temperature. The solvents were removed underhigh vacuum and the crude was purified by column chromatography (0→10%CHCl₃/10% 7N NH₃MeOH) to obtain1-Methyl-3-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(1-methylpiperidin-4-yl)urea29 as a beige solid (70.0 mg, 0.177 mmol, 10.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.58 (2H, br d, J=10.98 Hz), 1.73-1.85 (2H, m), 2.18 (2H,br s), 2.29 (3H, br s), 2.82 (3H, s), 2.89 (3H, s), 2.91-3.01 (2H, m),4.10-4.20 (1H, m), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.78Hz), 8.32 (1H, s), 8.36 (1H, s), 9.00 (1H, s), 9.16 (1H, s); ESIMS foundfor C₂₀H₂₄N₆OS m/z 397.2 (M+1).

Step 3

To the 2-(3-isocyanatoisoquinolin-6-yl)-5-methyl-1,3,4-thiadiazole (LX)(0.83 mmol) reaction solution from the procedure in Step 1 was addedtert-butyl ((3S,4S)-3-fluoropiperidin-4-yl)carbamate (LXII) (216 mg,0.99 mmol) and the mixture was stirred for 2 h at room temperatureslowly until the orange color disappears. The solvents were removedunder high vacuum and the crude was purified by column chromatography(0→10% CHCl₃/10% 7N NH₃MeOH) to produce tert-butyl((3S,4S)-3-fluoro-1-((6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)carbamoyl)piperidin-4-yl)carbamate(LXIII) as a beige solid (55 mg, 0.11 mmol, 13.7% yield).

Step 4

To a solution of TFA (0.79 mL, 10.28 mmol) in DCM (1 mL) was addedtert-butyl ((3S,4S)-3-fluoro-1-((6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)carbamoyl)piperidin-4-yl)carbamate (LXIII) (50 mg, 0.10 mmol) and then stirredovernight at room temperature. The solvent was evaporated under highvacuum and the residue was adsorbed on silica gel, purified by columnchromatography (0→10% 7N—NH₃-MeOH/CHCl₃). The pure fractions wereconcentrated and the solid was triturated with DCM/hexane, filtered anddried to obtain(3S,4S)-4-amino-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide33 as a beige solid (38.0 mg, 0.098 mmol, 95.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.28-1.39 (1H, m), 1.84 (2H, dt, J=13.10, 4.01 Hz), 2.82(3H, s), 2.85-2.94 (1H, m), 3.10-3.24 (2H, m), 3.84-3.94 (1H, m),4.11-4.29 (2H, m), 8.03 (1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d, J=8.51Hz), 8.30 (1H, s), 8.39 (1H, s), 9.17 (1H, s), 9.45 (1H, s); ESIMS foundfor C₁₈H₁₉FN₆OS m/z 387.1 (M+1).

Step 5

A mixture of(3S,4S)-4-amino-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 33 (35 mg, 0.09 mmol),formaldehyde (23.3 mg, 0.27 mmol) and catalytic HOAc in MeOH (5 mL) wasstirred for 30 min at room temperature. NaCNBH₃ (28.5 mg, 0.45 mmol) wasadded and the stirring was continued at room temperature for 2 h. Thereaction mixture was quenched with minimum amount of aqueous saturatedammonium chloride solution and concentrated under vacuum. The residuewas adsorbed on silica gel, purified by chromatography (0→10%7N.NH₃-MeOH/CHCl₃). The pure fractions were combined, concentrated andthe residue triturated from DCM/hexanes. The solid was collected byfiltration and further purified by HPLC using 0.1% Formicacid-MeCN/water. The pure fractions were dried and dissolved in MeOHfiltered through basic resin to obtain the free base of(3S,4S)-4-(dimethylamino)-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 34 as an off-white solid (25.0mg, 0.060 mmol, 66.6% yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.41-1.54(1H, m), 1.74-1.84 (1H, m), 2.28 (6H, s), 2.64 (1H, tdd, J=10.94, 10.94,8.71, 4.53 Hz), 2.82 (3H, s), 2.93-3.02 (1H, m), 3.05 (1H, ddd, J=12.97,9.13, 5.63 Hz), 4.00-4.11 (1H, m), 4.25-4.35 (1H, m), 4.63 (1H, dsxt,J=49.00, 4.10, 4.10, 4.10, 4.10, 4.10 Hz), 8.03 (1H, dd, J=8.51, 1.65Hz), 8.16 (1H, d, J=8.78 Hz), 8.30 (1H, s), 8.39 (1H, d, J=0.82 Hz),9.17 (1H, s), 9.48 (1H, s); ESIMS found for C₂₀H₂₃FN₆OS m/z 415.2 (M+1).

Example 8

Preparation ofN-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide(11) is depicted below in Scheme 20.

Steps 1

To a suspension of 6-bromoisoquinolin-3-amine (XV) (10 g, 44.83 mmol)and 2-chloroacetic anhydride (LXIV) (9.2 g, 53.79 mmol) in dry THF (100mL) was added TEA (15.62 mL, 112.07 mmol). The mixture was stirred atroom temperature for 16 h then poured into a mixture of aqueoussaturated NaHCO₃ (200 mL) and water (300 mL). The mixture was stirredfor an hour and the resulting solids were collected by filtration,air-dried and suspended in diethyl ether (400 mL), stirred for 30 min.The solid filtered and dried under high vacuo to obtainN-(6-bromoisoquinolin-3-yl)-2-chloroacetamide (LXV) as a brown solid(9.36 g, 31.25 mmol, 69.7% yield). ESIMS found for C₁₁H₈BrClN₂O m/z298.95 (M+1).

Step 2

A mixture of N-(6-bromoisoquinolin-3-yl)-2-chloroacetamide (LXV) (9.28g, 30.98 mmol), morpholine (8.04 mL, 92.94 mmol), and DIPEA (10.79 mL,61.96 mmol) in MeCN (100 mL) was heated to 90° C. for 16 h. The reactionmixture was filtered and the solid was dried under high vacuo to obtain8.45 grams of the product. The filtrate was concentrated, absorbed onsilica and purified by column chromatography (25→100% hexanes/EtOAc) toobtain another 1.75 g ofN-(6-bromoisoquinolin-3-yl)-2-morpholinoacetamide (LXVI) as a brownsolid (10.2 g, 28.05 mmol, 90.5% yield). ESIMS found for C₁₅H₁₆BrN₃O₂m/z 350.1 (M+1).

Step 3-4

A mixture of N-(6-bromoisoquinolin-3-yl)-2-morpholinoacetamide (LXIV)(15 g, 42.83 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (LIV) (16.3g, 64.25 mmol), Pd(dppf)Cl₂ (3.5 g, 4.28 mmol) and KOAc (12.61 g, 128.49mmol) was taken in dioxane (150 mL). N₂ gas was bubbled into the mixturefor 10 min which was then heated to 90° C. for 5 h. The reaction mixturewas filtered, washed with minimal dioxane and dried under vacuum toyield2-morpholino-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)acetamide(LXV) which was used without further purification.

Step 4

To a mixture of2-morpholino-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)acetamide(LXV) (675.4 mg, 1.7 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (LXVI)(0.55 g, 3.4 mmol) and SPhos Pd G4 (135 mg, 0.17 mmol) in dioxane (10mL) was added 2 N aqueous K₃PO₄ (1.7 mL, 3.4 mmol). N₂ gas was bubbledinto the mixture for 10 min and then heated to 90° C. for 24 h. Thereaction mixture was partitioned between EtOAc and aqueous saturatedNaHCO₃. Insoluble solids were removed by filtration and the organiclayer separated and washed with water and brine. The organic layer wasseparated, dried (MgSO₄) and concentration to dryness under vacuum. Thecrude was then combined with the insoluble solid, dissolved in a mixtureof chloroform/MeOH, absorbed on silica gel and was purified by columnchromatography (0%→70% CHCl₃/10% 7N NH₃MeOH in CHCl₃) to giveN-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide11 as a brown solid (170.0 mg, 0.482 mmol, 28.4% yield). ¹H NMR (499MHz, DMSO-d₆) δ ppm 2.55-2.61 (4H, m), 3.25 (2H, s), 3.63-3.69 (4H, m),4.14 (3H, s), 8.04 (1H, dd, J=8.51, 1.65 Hz), 8.13 (1H, d, J=8.78 Hz),8.33 (1H, s), 8.50 (1H, s), 8.74 (1H, s), 9.13 (1H, s), 10.07 (1H, s);ESIMS found for C₁₈H₂₀N₆O₂ m/z 353.2 (M+1).

Example 9

Preparation of2-(4-isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)isonicotinamide(9) is depicted below in Scheme 21.

Step 1

To a suspension of 6-bromoisoquinolin-1-d-3-amine (XIV) (200 mg, 0.89mmol), 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)isonicotinic acid(XXXIV) (329.1 mg, 1.07 mmol), DMAP (54.5 mg, 0.45 mmol) and HATU (407.2mg, 1.07 mmol) in DMF (4 mL) was added DIPEA (0.39 mL, 2.23 mmol). Theresulting mixture was at 80° C. for 1 h. Additional HATU (339 mg, 0.89mmol) was added and the mixture heated at 80° C. for an additional 2 h.The reaction mixture was cooled to room temperature and poured intowater. The resulting solid was filtered and dried under high vacuo toafford tert-butyl4-(4-((6-bromoisoquinolin-3-yl-1-d)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate(LXVII) as a brown solid (445 mg, 0.89 mmol, 97.1% yield). ESIMS foundfor C₂₄H₂₅DBrN₅O₃ m/z 513.1 (⁷⁹BrM+H).

Step 2

A mixture of tert-butyl4-(4-((6-bromoisoquinolin-3-yl-1-d)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate(LXVII) (440 mg, 0.86 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(LXVIII) (196.2 mg, 0.94 mmol), Pd(dppf)Cl₂ (49 mg, 0.06 mmol) and 2 Maqueous K₃PO₄ (1.07 mL, 2.14 mmol) in dioxane (5 mL) was purged withnitrogen and then stirred at 90° C. in a sealed tube for 3 h. Thereaction was cooled to room temperature and concentrated under vacuum.The crude product was purified by flash column chromatography (0→5%MeOH/CHCl₃) to afford tert-butyl4-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate(LXIX) as a brown foam (410 mg, 0.80 mmol, 93.0% yield). ESIMS found forC₂₈H₃₀DN₇O₃ m/z 515.3 (M+H).

Step 3

To a suspension of tert-butyl4-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate(LXIX) (410 mg, 0.80 mmol) in MeOH (5 mL) was added hydrogen chloride (4M in dioxane) (1.0 mL, 3.98 mmol). The solution was stirred at 60° C.for 1 h and then the reaction mixture was concentrated under highvacuum. The crude product was purified by silica gel chromatography(0→10% 7 N NH₃-MeOH/CHCl₃) to giveN-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(piperazin-1-yl)isonicotinamide (LXX) as an off white solid (250 mg, 0.60 mmol, 75.7%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.77-2.84 (4H, m), 3.48-3.57(4H, m), 3.91 (3H, s), 7.13 (1H, dd, J=5.08, 1.24 Hz), 7.42 (1H, s),7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s),8.14 (1H, s), 8.25 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.59 (1H, s), 11.03(1H, s); ESIMS found for C₂₃H₂₂[²H]N₇O m/z 415. (M+1).

Step 4

To a mixture ofN-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(piperazin-1-yl)isonicotinamide (LXX) (63 mg, 0.15 mmol) and HOAc (0.03 mL, 0.46 mmol)in a mixture of acetone (1 mL) and MeOH (2 mL) was added NaCNBH₃ (28.6mg, 0.46 mmol). The mixture was stirred at 50° C. for 3 h. The mixturewas concentrated and the residue purified by chromatography (0→6% 7NNH₃-MeOH/CHCl₃) to produce2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)isonicotinamide9 as a white solid (53.0 mg, 0.116 mmol, 76.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.01 (6H, d, J=6.59 Hz), 2.52-2.58 (4H, m), 2.66-2.76(1H, m), 3.55-3.62 (4H, m), 3.91 (3H, s), 7.15 (1H, dd, J=5.21, 1.10Hz), 7.44 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51Hz), 8.11 (1H, d, J=0.82 Hz), 8.14 (1H, s), 8.25 (1H, d, J=4.94 Hz),8.38 (1H, s), 8.59 (1H, s), 11.04 (1H, s); ESIMS found for C₂₆H₂₈[²H]N₇Om/z 457.25 (M+1).

Example 10

Preparation ofN-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-2,2,5,5-d₄)isonicotinamide(79) is depicted below in Scheme 22.

Step 1

A mixture of 6-bromoisoquinolin-3-amine (XV) (2.57 g, 11.52 mmol),1-methyl-5-(tributylstannyl)-1H-imidazole (LXXI) (Combi-blocks) (4.28 g,11.53 mmol), Pd(PPh₃)₄ (1.39 g, 1.2 mmol) in dioxane (57.6 mL) waspurged with N₂ gas for 10 min and then heated to 90° C. overnight. Thesolvent was evaporated under high vacuum and the residue was purified bycolumn chromatography (0→10% MeOH/CHCl₃) to give6-(3-methylimidazol-4-yl)isoquinolin-3-amine (LXXII) as an olive greensolid (2.32 g, 9.83 mmol, 85.3% yield). ESIMS found for C₁₃H₁₂N₄ m/z225.1 (M+H).

Step 2

To a suspension of 6-(3-methylimidazol-4-yl)isoquinolin-3-amine (LXXII)(500 mg, 2.23 mmol), 2-fluoroisonicotinic acid (LXXIII) (377.5 mg, 2.68mmol), DMAP (136 mg, 1.11 mmol) and HATU (1.02 g, 2.68 mmol) in DMF (8mL) was added DIPEA (0.97 mL, 5.57 mmol). The resulting mixture wasstirred at 80° C. for 1 h and then cooled to room temperature. Water wasadded and the resulting solid was filtered and dried under high vacuo toafford2-fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide(LXXIV) as a beige solid (675 mg, 1.94 mmol, 87.2% yield). ESIMS foundfor C₁₉H₁₄FN₅O m/z 348.1 (M+H).

Step 3

A mixture of 2-fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide (LXXIV) (80 mg, 0.23 mmol), DIPEA (0.12 mL, 0.69 mmol)and pyrrolidine-2,2,5,5-d₄ (LXXV) (0.06 mL, 0.69 mmol) in DMF (2 mL) washeated to 100° C. for 21 h. The reaction mixture was concentrated andthe crude product purified by silica gel chromatography (0→6% 7 NNH₃-MeOH/CHCl₃). The fractions containing the product were concentratedand the residue triturated in ether. The resulting solid was filteredand dried under high vacuo to affordN-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-2,2,5,5-d₄)isonicotinamide79 as a beige solid (58.0 mg, 0.144 mmol, 62.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.96 (4H, s), 3.85 (3H, s), 7.06 (1H, dd, J=5.21, 1.37Hz), 7.07-7.12 (1H, m), 7.33 (1H, d, J=1.10 Hz), 7.74 (1H, dd, J=8.51,1.65 Hz), 7.81 (1H, s), 8.10 (1H, d, J=0.82 Hz), 8.15 (1H, d, J=8.78Hz), 8.18-8.24 (1H, m), 8.69 (1H, s), 9.22 (1H, s), 11.05 (1H, s); ESIMSfound for C₂₃H₁₈[²H₄]N₆O m/z 403.15 (M+1).

Example 11

Preparation oftrans-N-(8-fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide(101) is depicted below in Scheme 23.

Step 1

A mixture of 6-bromo-8-fluoroisoquinolin-3-amine (XXXV) (300 mg, 1.24mmol), DIPEA (1.08 mL, 6.22 mmol), HATU (591.5 mg, 1.56 mmol) and DMAP(15.2 mg, 0.12 mmol), andtrans-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (LXXVI) (290 mg,1.56 mmol) in DMF (5 mL). The reaction was heated to 80° C. overnight.Additional HATU (235 mg, 0.62 mmol) was added and the mixture wasstirred for another 5 h at 80° C. The reaction mixture was concentratedand the residue partitioned between EtOAc and aqueous saturated NaHCO₃.The organic layer was separated and washed with water and brine. Thecrude was purified by column chromatography (10→80% EtOAc/hexanes) toobtain methyltrans-4-((6-bromo-8-fluoroisoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylate(LXXVII) as a beige solid (330 mg, 0.80 mmol, 64.8% yield). ESIMS foundfor C₁₈H₁₈BrFN₂O₃ m/z 409.05 (⁷⁹BrM+1).

Step 2

A suspension of methyltrans-4-((6-bromo-8-fluoroisoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylate (LXXVII) (330 mg, 0.81 mmol) in a mixture ofMeOH (1 mL) and THF (2 mL) was added 2 M aqueous NaOH (0.81 mL, 1.61mmol). The reaction was heated to 50° C. for 2 h. The mixture wasconcentrated and the residue taken in water and acidified with 1N HCl.The resulting solid was collected by filtration and dried under vacuumoven at 50° C. overnight to obtaintrans-4-((6-bromo-8-fluoroisoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylicacid (LXXVIII) as an off-white solid (285 mg, 0.72 mmol, 89.4% yield).ESIMS found for C₁₇H₁₆BrFN₂O₃ m/z 395.0 (⁷⁹BrM+1).

Step 3

A mixture oftrans-4-((6-bromo-8-fluoroisoquinolin-3-yl)carbamoyl)cyclohexane-1-carboxylicacid (LXXVIII) (280 mg, 0.71 mmol), HATU (255.9 mg, 0.67 mmol) and DIPEA(0.25 mL, 1.42 mmol) in DMF (3 mL) was stirred for 10 min. DMAP (108.6mg, 0.89 mmol) was added and the mixture was stirred for 4 h at roomtemperature. The reaction mixture was poured into water (30 mL), thesolid was collected by filtration, washed with aqueous saturated NaHCO₃,water and dried under vacuum over at 50° C. for 4 h to obtaintrans-N-(6-bromo-8-fluoroisoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide (LXXIX) as a pale yellow solid (270 mg, 0.57mmol, 79.8% yield) which was used for next step without purification.ESIMS found for C₂₂H₂₆BrFN₄O₂ m/z 477.15 (⁷⁹BrM+1).

Step 4

To a mixture oftrans-N-(6-bromo-8-fluoroisoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide (LXXIX) (135 mg, 0.28 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (XLVII)(73.9 mg, 0.35 mmol), and Pd(dppf)Cl₂ (23.1 mg, 0.03 mmol) in MeCN (1.5mL) was added 2 M aqueous solution of K₂CO₃ (0.35 mL, 0.71 mmol). N₂ gaswas bubbled into the mixture for 10 min followed by heating at 110° C.for 30 min using microwave (MW) irradiation. The organic layer wascarefully separated, absorbed on silica gel and purified by flash columnchromatography (10-80% CHCl₃/10% 7 N NH₃MeOH in CHCl₃). The purefractions were combined, concentrated, the solid was suspended in EtOAc,sonicated and were collected by filtration, dried under high vacuo toobtaintrans-N-(8-Fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide 101 as an off-white solid (83.0 mg, 0.173mmol, 61.2% yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.36-1.47 (2H, m),1.51-1.62 (2H, m), 1.72 (2H, br d, J=11.25 Hz), 1.89 (2H, br d, J=10.15Hz), 2.18 (3H, s), 2.23 (2H, br s), 2.30 (2H, br s), 2.53 (3H, s),2.55-2.60 (1H, m), 2.61-2.68 (1H, m), 3.44 (2H, br s), 3.50 (2H, br s),7.62-7.68 (1H, m), 7.84 (1H, s), 7.96 (1H, s), 8.57 (1H, s), 9.22 (1H,s), 10.67 (1H, s); ESIMS found for C₂₆H₃₀FN₅O₃ m/z 480.3 (M+1).

Example 12

Preparation oftrans-4-amino-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide(149),trans-4-((1,3-difluoropropan-2-yl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide(124) andtrans-4-(2-(fluoromethyl)aziridin-1-yl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide(154) are depicted below in Scheme 24.

Step 1

To a mixture of 6-(2-methyloxazol-5-yl)isoquinolin-3-amine (XLVII) (370mg, 1.64 mmol), HATU (0.94 g, 2.46 mmol), and DMAP (20.07 mg, 0.16 mmol)in DMF (5 mL) was stirred for 10 min before adding DIPEA (0.57 mL, 3.29mmol) and trans-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylicacid (XXXVI) (400 mg, 1.64 mmol). The mixture was stirred at 60° C.overnight. The solvent was evaporated under high vacuum, the residue wastaken up in EtOAc and washed with aqueous saturated NaHCO₃, water andthen with brine. The organic layer was separated and dried (MgSO₄)before evaporation to dryness. The crude product was purified by silicagel chromatography (0→10% MeOH/CHCl₃). The fractions containing theproduct were concentrated and triturated with DCM/hexanes, filtered anddried under high vacuum to obtain tert-butyl(trans-4-((6-(2-methyloxazol-5-yl)isoquinolin-3-yl)carbamoyl)cyclohexyl)carbamate(LXXX) as a beige solid (723 mg, 1.60 mmol, 97.7% yield). ESIMS foundfor C₂₅H₃₀N₄O₄ m/z 451.3 (M+1).

Step 2

To a solution of TFA (1.71 mL, 22.2 mmol) in DCM (2 mL) was addedtert-butyl(trans-4-((6-(2-methyloxazol-5-yl)isoquinolin-3-yl)carbamoyl)cyclohexyl)carbamate(LXXX) (500 mg, 1.11 mmol). The mixture was stirred overnight at roomtemperature. The solvent was evaporated under high vacuum and theresidue was adsorbed on silica gel, purified by column chromatography(0→10% 7N—NH₃-MeOH/CHCl₃). The pure fractions were concentrated and thesolid was triturated with DCM/hexane, filtered and dried to producetrans-4-Amino-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide149 as a beige solid (370.0 mg, 1.056 mmol, 95.1% yield). ¹H NMR (499MHz, DMSO-d₆) δ ppm 0.98-1.11 (2H, m), 1.43-1.54 (2H, m), 1.82 (4H, brd, J=11.53 Hz), 2.43-2.49 (1H, m), 2.52 (1H, br s), 2.53 (3H, s), 7.78(1H, s), 7.79-7.83 (1H, m), 8.06-8.12 (2H, m), 8.49 (1H, s), 9.10 (1H,s), 10.49 (1H, s); ESIMS found for C₂₀H₂₂N₄O₂ m/z 351.2 (M+1).

Step 3

A mixture of trans-4-Amino-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 149 (115 mg, 0.33 mmol),1,3-difluoropropan-2-one (LXXXI) (0.03 mL, 0.36 mmol) and catalytic HOAcin MeOH (1 mL) was stirred for 30 min at room temperature. NaCNBH₃ (45.4mg, 0.72 mmol) was added and the reaction was stirred for 24 h at roomtemperature. Reaction mixture was quenched with minimum amount ofaqueous saturated ammonium chloride solution, concentrated under vacuum.The residue was adsorbed on silica gel and purified by chromatography(0→10% 7N—NH₃-MeOH/CHCl₃). The pure fractions were combined,concentrated and further purified by preparative TLC (6% 7 NNH₃MeOH/CHCl₃) to obtaintrans-4-((1,3-Difluoropropan-2-yl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 124 as an off-white solid (20.0 mg, 0.047mmol, 14.2% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98-1.09 (2H, m),1.42-1.54 (2H, m), 1.65 (1H, br s), 1.82-1.89 (2H, m), 1.91-1.98 (2H,m), 2.51-2.60 (1H, m), 2.53 (3H, s), 4.30-4.51 (4H, m), 7.78 (1H, s),7.81 (1H, dd, J=8.64, 1.51 Hz), 8.09 (2H, dd, J=4.67, 3.84 Hz), 8.50(1H, s), 9.10 (1H, s), 10.51 (1H, s); ESIMS found for C₂₃H₂₆F₂N₄O₂ m/z429.2 (M+1) andtrans-4-(2-(fluoromethyl)aziridin-1-yl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 154 as an off-white solid(10.0 mg, 0.025 mmol, 7.4% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.17-1.33 (4H, m), 1.35-1.45 (3H, m), 1.87 (4H, br d, J=9.88 Hz),2.51-2.59 (1H, m), 2.53 (3H, s), 3.97-4.14 (2H, m), 4.36-4.50 (1H, m),7.76-7.79 (1H, m), 7.80 (1H, dd, J=8.64, 1.51 Hz), 8.06-8.13 (2H, m),8.49 (1H, s), 9.10 (1H, s), 10.51 (1H, s); ESIMS found for C₂₃H₂₅FN₄O₂m/z 409.2 (M+1).

Example 13

Preparation ofN-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide(129) is depicted below in Scheme 25.

Step 1

To a suspension of 6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-amine(LVI) (200 mg, 0.83 mmol), TEA (0.58 mL, 4.13 mmol), DMAP (10.1 mg, 0.08mmol) in THF (20 mL) was added diphosgene (0.12 mL, 0.99 mmol) and themixture was stirred at room temperature for 1 h.1-Methyl-4-(piperidin-4-yl)piperazine (LXXXII) (454 mg, 2.48 mmol) wasthen added and the mixture was stirred at room temperature for 1 h. Thereaction was filtered, and the filtrates were absorbed onto Celite andpurified by column chromatography (10-60% CHCl₃/10% 7 N NH₃MeOH inCHCl₃) followed by preparative TLC to obtainN-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide 129 as an off-white solid (45.0 mg, 0.100 mmol,12.1% yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.34 (2H, qd, J=11.94,3.98 Hz), 1.77 (2H, br d, J=10.98 Hz), 2.13 (3H, s), 2.30 (4H, br s),2.36-2.43 (1H, m), 2.43-2.54 (4H, m), 2.77-2.87 (2H, m), 2.82 (3H, s),4.23 (2H, br d, J=13.17 Hz), 8.02 (1H, dd, J=8.78, 1.65 Hz), 8.15 (1H,d, J=8.51 Hz), 8.30 (1H, s), 8.37 (1H, d, J=0.82 Hz), 9.15 (1H, s), 9.30(1H, s); ESIMS found for C₂₃H₂₉N₇OS m/z 452.2 (M+1).

Example 14

Preparation of1-methyl-4-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine 1-oxide (224) and1-methyl-4-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)-1-oxidopyridin-2-yl)piperazine 1-oxide (225) are depictedbelow in Scheme 26.

Step 1

To a suspension2-(4-methylpiperazin-1-yl)-N-[6-(1-methyltriazol-4-yl)isoquinolin-3-yl]pyridine-4-carboxamide(LXXXIII) (100 mg, 0.23 mmol) in DCM (8 mL) was added MCPBA (78.5 mg,0.35 mmol). The mixture was stirred at room temperature for 5 h andconcentrated. The crude product was purified by silica gelchromatography (0-18% 7 N NH₃-MeOH/CHCl₃). The fractions containing theproduct were concentrated and the residue triturated in ether. Theresulting solid was filtered and dried under high vacuo to afford1-methyl-4-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine1-oxide (224) as a beige solid (75 mg, 0.17 mmol, 72.3% yield). ¹H NMR(499 MHz, DMSO-d₆) δ ppm 2.99 (2H, br d, J=10.70 Hz), 3.11 (3H, s), 3.41(3H, td, J=11.46, 3.16 Hz), 3.62-3.73 (2H, m), 4.15 (3H, s), 4.25 (2H,br d, J=13.45 Hz), 7.21 (1H, dd, J=5.21, 1.10 Hz), 7.56 (1H, s), 8.08(1H, dd, J=8.51, 1.37 Hz), 8.18 (1H, d, J=8.51 Hz), 8.29 (1H, d, J=5.21Hz), 8.39 (1H, s), 8.67 (1H, s), 8.76 (1H, s), 9.22 (1H, s), 11.17 (1H,s); ESIMS found for C₂₃H₂₄N₈O₂ m/z 445.2 (M+1).

In addition, the double oxidation side product was isolated as a solidwhich was triturated in a saturated NaHCO₃ solution, filtered and driedunder high vacuo to afford1-methyl-4-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)-1-oxidopyridin-2-yl)piperazine 1-oxide (225) as a white solid(12 mg, 0.03 mmol, 11.2% yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.88(2H, br d, J=11.25 Hz), 3.03 (2H, br d, J=11.53 Hz), 3.22 (3H, s), 4.13(3H, s), 4.34 (2H, br t, J=10.98 Hz), 4.81-4.90 (2H, m), 7.85 (1H, br d,J=8.23 Hz), 7.98 (1H, br d, J=7.96 Hz), 8.12 (1H, br d, J=4.39 Hz), 8.15(1H, br s), 8.54 (1H, s), 8.56 (1H, br d, J=4.94 Hz), 8.70 (1H, s), 9.04(1H, s), 9.06 (1H, s), 11.44 (1H, br s); ESIMS found for C₂₃H₂₄N₈O₃ m/z461.1 (M+1).

The following compounds were prepared in accordance with the proceduresdescribed in the above Examples 1-13.

trans-4-(Dimethylamino)-N-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 1.

White solid (285.0 mg, 0.721 mmol, 71.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.12-1.26 (2H, m), 1.47 (2H, qd, J=12.67, 2.61 Hz),1.80-1.97 (4H, m), 2.10-2.22 (1H, m), 2.18 (6H, s), 2.44-2.49 (1H, m),3.89 (3H, s), 7.58 (1H, dd, J=12.08, 1.10 Hz), 7.91 (1H, s), 8.11 (1H,s), 8.39 (1H, s), 8.48 (1H, s), 9.15 (1H, s), 10.56 (1H, s); ESIMS foundfor C₂₂H₂₆FN₅O m/z 396.2 (M+1).

trans-4-(Dimethylamino)-N-(7-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 2.

Beige solid (4.0 mg, 0.010 mmol, 5.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.14-1.26 (2H, m), 1.42-1.53 (2H, m), 1.83-1.96 (4H, m), 2.11-2.21(1H, m), 2.18 (6H, s), 2.42-2.49 (1H, m), 3.93 (3H, s), 7.89 (1H, d,J=11.53 Hz), 8.10 (1H, s), 8.26 (1H, d, J=7.41 Hz), 8.30 (1H, d, J=2.74Hz), 8.48 (1H, s), 9.03 (1H, s), 10.44 (1H, s); ESIMS found forC₂₂H₂₆FN₅O m/z 396.2 (M+1).

trans-N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide3.

White solid (51.0 mg, 0.117 mmol, 50.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.16-1.28 (2H, m), 1.42-1.55 (2H, m), 1.91 (4H, brt,J=12.35 Hz), 2.16-2.28 (1H, m), 2.44-2.49 (5H, m), 3.51-3.60 (4H, m),3.89 (3H, s), 7.58 (1H, dd, J=12.08, 1.37 Hz), 7.91 (1H, s), 8.11 (1H,s), 8.39 (1H, s), 8.48 (1H, s), 9.15 (1H, s), 10.57 (1H, s); ESIMS foundfor C₂₄H₂₈FN₅O₂ m/z 438.2 (M+1).

2-(1-Isobutylpyrrolidin-3-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)acetamide4.

White solid (25.0 mg, 0.064 mmol, 14.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, dd, J=6.59, 1.37 Hz), 1.43 (1H, dq, J=12.86,6.32 Hz), 1.67 (1H, dquin, J=13.45, 6.66, 6.66, 6.66, 6.66 Hz),1.88-2.01 (1H, m), 2.15 (3H, br s), 2.40-2.47 (1H, m), 2.52 (2H, s),2.53-2.59 (1H, m), 2.67 (1H, br s), 3.90 (3H, s), 7.74 (1H, dd, J=8.51,1.65 Hz), 7.99 (1H, d, J=8.78 Hz), 8.05 (1H, d, J=0.82 Hz), 8.08 (1H,s), 8.35 (1H, s), 8.44 (1H, s), 9.02 (1H, s), 10.49 (1H, s); ESIMS foundfor C₂₃H₂₉N₅O m/z 392.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide5.

Off-white solid (130.0 mg, 0.386 mmol, 58.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.53 (2H, qd, J=12.21, 3.98 Hz), 1.67-1.74 (2H, m),2.43-2.49 (2H, m), 2.60-2.68 (1H, m), 2.94-3.01 (2H, m), 3.90 (3H, s),7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.03 (1H, s),8.08 (1H, s), 8.35 (1H, s), 9.02 (1H, s), 10.40 (1H, s); ESIMS found forC₁₉H₂₀[²H]N₅O m/z 337.2 (M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide6.

White solid (35.0 mg, 0.089 mmol, 50.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (6H, d, J=6.59 Hz), 1.62-1.73 (2H, m), 1.73-1.81(3H, m), 1.82-1.91 (2H, m), 2.02 (2H, d, J=7.41 Hz), 2.52-2.57 (1H, m),2.86 (2H, br d, J=11.53 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.64, 1.51Hz), 8.00 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.35 (1H, s),9.02 (1H, s), 10.45 (1H, s); ESIMS found for C₂₃H₂₈[²H]N₅O m/z 393.25(M+1).

1-Isobutyl-N-(6-(1-methyl-1H-pyrazol-3-yl)isoquinolin-3-yl)piperidine-4-carboxamide7.

White solid (10.0 mg, 0.026 mmol, 19.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.86 (7H, d, J=6.59 Hz), 1.63-1.73 (2H, m), 1.74-1.81(3H, m), 1.86 (2H, br t, J=10.84 Hz), 2.02 (2H, d, J=7.41 Hz), 2.51-2.60(1H, m), 2.86 (2H, br d, J=11.25 Hz), 3.93 (3H, s), 6.93 (1H, d, J=2.20Hz), 7.80 (1H, d, J=2.20 Hz), 7.96-8.01 (1H, m), 8.01-8.06 (1H, m), 8.21(1H, s), 8.49 (1H, s), 9.07 (1H, s), 10.48 (1H, s); ESIMS found forC₂₃H₂₉N₅O m/z 392.2 (M+1).

2-(4-Ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)isonicotinamide8.

White solid (20.0 mg, 0.045 mmol, 28.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.05 (3H, t, J=7.14 Hz), 2.38 (2H, q, J=7.14 Hz),2.45-2.49 (4H, m), 3.57-3.64 (4H, m), 3.91 (3H, s), 7.16 (1H, dd,J=5.08, 0.96 Hz), 7.46 (1H, s), 7.81 (1H, dd, J=8.51, 1.37 Hz), 8.07(1H, d, J=8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.25 (1H, d, J=4.94 Hz),8.38 (1H, s), 8.59 (1H, s), 11.05 (1H, br s); ESIMS found forC₂₅H₂₆[²H]N₇O m/z 443.2 (M+1).

2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)isonicotinamide9.

White solid (53.0 mg, 0.116 mmol, 76.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.01 (6H, d, J=6.59 Hz), 2.52-2.58 (4H, m), 2.66-2.76(1H, m), 3.55-3.62 (4H, m), 3.91 (3H, s), 7.15 (1H, dd, J=5.21, 1.10Hz), 7.44 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51Hz), 8.11 (1H, d, J=0.82 Hz), 8.14 (1H, s), 8.25 (1H, d, J=4.94 Hz),8.38 (1H, s), 8.59 (1H, s), 11.04 (1H, s); ESIMS found for C₂₆H₂₈[²H]N₇Om/z 457.25 (M+1).

trans-4-(Dimethylamino)-N-(8-fluoro-6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 10.

White solid (8.0 mg, 0.020 mmol, 4.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.13-1.25 (2H, m), 1.48 (2H, qd, J=12.67, 2.88 Hz), 1.83-1.90 (2H,m), 1.90-1.97 (2H, m), 2.10-2.21 (1H, m), 2.18 (6H, s), 2.45-2.49 (1H,m), 4.14 (3H, s), 7.77 (1H, dd, J=11.53, 1.10 Hz), 8.16 (1H, s), 8.56(1H, s), 8.76 (1H, s), 9.24 (1H, s), 10.65 (1H, s); ESIMS found forC₂₁H₂₅FN₆O m/z 397.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-morpholinoacetamide11.

Brown solid (170.0 mg, 0.482 mmol, 28.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.61 (4H, m), 3.25 (2H, s), 3.63-3.69 (4H, m), 4.14(3H, s), 8.04 (1H, dd, J=8.51, 1.65 Hz), 8.13 (1H, d, J=8.78 Hz), 8.33(1H, s), 8.50 (1H, s), 8.74 (1H, s), 9.13 (1H, s), 10.07 (1H, s); ESIMSfound for C₁₈H₂₀N₆O₂ m/z 353.2 (M+1).

trans-N-(6-(2-Methyloxazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide12.

Beige solid (2.5.0 mg, 0.006 mmol, 5.1% yield). ¹H NMR (499 MHz,CHLOROFORM-d) δ ppm 0.81-0.92 (2H, m), 1.31-1.42 (2H, m), 1.63-1.73 (2H,m), 2.04-2.12 (2H, m), 2.12-2.21 (2H, m), 2.23-2.40 (2H, m), 2.31 (3H,s), 2.49 (3H, br s), 2.60 (3H, s), 2.65 (3H, br s), 7.40 (1H, s), 7.67(1H, dd, J=8.51, 1.65 Hz), 7.90 (1H, d, J=8.51 Hz), 8.00 (1H, s), 8.02(1H, s), 8.59 (1H, s), 8.92 (1H, s); ESIMS found for C₂₅H₃₁N₅O₂ m/z434.25 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)morpholine-4-carboxamide13.

White solid (35.0 mg, 0.100 mmol, 15.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.39 (3H, s), 3.46-3.55 (4H, m), 3.59-3.64 (4H, m), 3.65(3H, s), 7.09 (1H, s), 7.54 (1H, dd, J=8.51, 1.65 Hz), 7.84 (1H, s),8.05 (1H, d, J=8.51 Hz), 8.22 (1H, s), 9.07 (1H, s), 9.26 (1H, s); ESIMSfound for C₁₉H₂₁N₅O₂ m/z 352.2 (M+1).

N-(6-(4-Methyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-2-morpholinoacetamide14.

Beige solid (34.0 mg, 0.097 mmol, 25.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.63 (4H, m), 3.27 (2H, s), 3.63-3.69 (4H, m), 3.88(3H, s), 7.93 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d, J=8.51 Hz), 8.33(1H, d, J=0.82 Hz), 8.62 (1H, s), 8.66 (1H, s), 9.24 (1H, s), 10.16 (1H,s); ESIMS found for C₈H₂₀N₆O₂ m/z 353.2 (M+1).

N-(6-(4,5-Dimethyl-4H-1,2,4-triazol-3-yl)isoquinolin-3-yl)-2-morpholinoacetamide15.

White solid (51.0 mg, 0.139 mmol, 36.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.45 (3H, s), 2.55-2.62 (4H, m), 3.27 (2H, s), 3.61-3.68(4H, m), 3.71 (3H, s), 7.85 (1H, dd, J=8.51, 1.65 Hz), 8.21 (1H, d,J=8.51 Hz), 8.25 (1H, s), 8.61 (1H, s), 9.23 (1H, s), 10.16 (1H, s);ESIMS found for C₁₉H₂₂N₆O₂ m/z 367.2 (M+1).

trans-4-(Methylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 16.

Off-white solid (131.0 mg, 0.360 mmol, 74.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.93-1.04 (2H, m), 1.48 (2H, qd, J=12.85, 3.16 Hz), 1.86(2H, br d, J=11.25 Hz), 1.95 (2H, br dd, J=13.17, 3.02 Hz), 2.22 (1H,tt, J=10.94, 4.01 Hz), 2.28 (3H, s), 2.53 (3H, s), 7.78 (1H, s),7.79-7.84 (1H, m), 8.06-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.49(1H, s); ESIMS found for C₂₁H₂₄N₄O₂ m/z 365.2 (M+1).

trans-4-(Dimethylamino)-N-(8-fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide17.

Beige solid (115.0 mg, 0.290 mmol, 57.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.13-1.25 (2H, m), 1.47 (2H, qd, J=12.76, 2.61 Hz),1.83-1.90 (2H, m), 1.90-1.96 (2H, m), 2.09-2.22 (1H, m), 2.18 (6H, s),2.45-2.49 (1H, m), 2.53 (3H, s), 7.64 (1H, dd, J=11.39, 0.96 Hz), 7.83(1H, s), 7.95 (1H, s), 8.56 (1H, s), 9.22 (1H, s), 10.65 (1H, s); ESIMSfound for C₂₂H₂₅FN₄O₂ m/z 397.2 (M+1).

trans-4-(Dimethylamino)-N-(7-fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide18.

Beige solid (20.0 mg, 0.050 mmol, 26.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.13-1.24 (2H, m), 1.41-1.54 (2H, m), 1.82-1.95 (4H, m),2.09-2.20 (1H, m), 2.18 (6H, s), 2.43-2.49 (1H, m), 2.57 (3H, s), 7.59(1H, d, J=4.67 Hz), 8.01 (1H, d, J=11.53 Hz), 8.23 (1H, d, J=6.86 Hz),8.56 (1H, s), 9.10 (1H, s), 10.52 (1H, s); ESIMS found for C₂₂H₂₅FN₄O₂m/z 397.2 (M+1).

trans-N-(8-Fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide19.

White solid (30.0 mg, 0.068 mmol, 29.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.15-1.28 (2H, m), 1.42-1.54 (2H, m), 1.92 (4H, brt,J=12.76 Hz), 2.15-2.28 (1H, m), 2.46-2.49 (4H, m), 2.53 (3H, s),3.52-3.60 (4H, m), 7.65 (1H, dd, J=11.53, 1.10 Hz), 7.84 (1H, s), 7.95(1H, s), 8.56 (1H, s), 9.22 (1H, s), 10.66 (1H, s) ESIMS found forC₂₄H₂₇FN₄O₃ m/z 439.2 (M+1).

1-(2,2-Difluoropropyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide 20.

White solid (26.0 mg, 0.063 mmol, 25.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.63 (3H, t, J=19.21 Hz), 1.67-1.74 (2H, m), 1.75-1.80(2H, m), 2.22 (2H, td, J=11.66, 2.47 Hz), 2.52-2.58 (1H, m), 2.53 (3H,s), 2.71 (2H, t, J=14.00 Hz), 2.91-2.99 (2H, m), 7.78 (1H, s), 7.81 (1H,dd, J=8.51, 1.65 Hz), 8.06-8.13 (2H, m), 8.51 (1H, s), 9.10 (1H, s),10.55 (1H, s); ESIMS found for C₂₂H₂₄F₂N₄O₂ m/z 415.2 (M+1).

trans-4-Amino-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 21.

White solid (210.0 mg, 0.572 mmol, 68.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.99-1.12 (2H, m), 1.42-1.54 (2H, m), 1.57-1.72 (1H, m),1.79-1.88 (4H, m), 2.45-2.55 (1H, m), 2.82 (3H, s), 8.08 (1H, dd,J=8.51, 1.65 Hz), 8.18 (1H, d, J=8.51 Hz), 8.43 (1H, s), 8.60 (1H, s),9.20 (1H, s), 10.57 (1H, s); ESIMS found for C₁₉H₂₁N₅OS m/z 368.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide22.

White solid (22.0 mg, 0.056 mmol, 25.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.13-1.26 (2H, m), 1.48 (2H, qd, J=12.67, 2.88 Hz),1.83-1.90 (2H, m), 1.93 (2H, br d, J=11.53 Hz), 2.11-2.16 (1H, m), 2.18(6H, s), 2.83 (3H, s), 8.08 (1H, dd, J=8.51, 1.65 Hz), 8.18 (1H, d,J=8.51 Hz), 8.43 (1H, d, J=0.82 Hz), 8.61 (1H, s), 9.21 (1H, s), 10.58(1H, s); ESIMS found for C₂₁H₂₅N₅OS m/z 396.2 (M+1).

trans-N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide23.

Off-white solid (16.0 mg, 0.037 mmol, 13.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.16-1.29 (2H, m), 1.43-1.56 (2H, m), 1.86-1.97 (4H, m),2.17-2.26 (1H, m), 2.46-2.49 (4H, m), 2.51-2.54 (1H, m), 2.82 (3H, s),3.52-3.60 (4H, m), 8.08 (1H, dd, J=8.51, 1.65 Hz), 8.18 (1H, d, J=8.51Hz), 8.44 (1H, d, J=0.82 Hz), 8.61 (1H, s), 9.21 (1H, s), 10.59 (1H, s);ESIMS found for C₂₃H₂₇N₅O₂S m/z 438.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide24.

Light green solid (105.0 mg, 0.297 mmol, 22.8% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.93-2.02 (2H, m), 2.05-2.20 (5H, m), 2.22 (3H, s),2.71-2.77 (2H, m), 2.83 (3H, s), 8.15 (1H, dd, J=8.64, 1.78 Hz), 8.24(1H, d, J=8.51 Hz), 8.52 (1H, s), 8.59 (1H, s), 9.27 (1H, s), 10.08 (1H,d, J=4.12 Hz); ESIMS found for C₁₈H₁₉N₅OS m/z 354.1 (M+1).

4-Fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide25.

Beige solid (64.0 mg, 0.172 mmol, 45.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.80-1.90 (2H, m), 1.98 (1H, td, J=12.97, 5.08 Hz), 2.06(1H, td, J=12.97, 5.08 Hz), 2.19 (1H, br s), 2.75 (2H, td, J=12.21, 2.20Hz), 2.83 (3H, s), 2.87-2.94 (2H, m), 8.15 (1H, dd, J=8.51, 1.65 Hz),8.24 (1H, d, J=8.51 Hz), 8.53 (1H, d, J=0.82 Hz), 8.59 (1H, s), 9.26(1H, s), 9.98 (1H, br d, J=3.57 Hz); ESIMS found for C₁₈H₁₈FN₅OS m/z372.1 (M+1).

4-Fluoro-1-methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide 26.

White solid (15.0 mg, 0.039 mmol, 24.1% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 2.02-2.10 (2H, m), 2.28-2.45 (4H, m), 2.36 (3H, s),2.84-2.92 (2H, m), 2.86 (3H, s), 8.13-8.20 (2H, m), 8.42 (1H, s), 8.61(1H, s), 9.15 (1H, s); ESIMS found for C₁₉H₂₀FN₅OS m/z 386.15 (M+1).

1-(2,2-Difluoroethyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide27.

Beige solid (20.0 mg, 0.048 mmol, 53.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.74 (2H, m), 1.76-1.83 (2H, m), 2.14-2.25 (2H, m),2.52-2.61 (1H, m), 2.73 (2H, td, J=15.71, 4.25 Hz), 2.83 (3H, s), 2.96(2H, br d, J=11.53 Hz), 6.14 (1H, tt, J=56.10, 4.40 Hz), 8.09 (1H, dd,J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.45 (1H, s), 8.62 (1H, s),9.21 (1H, s), 10.64 (1H, s); ESIMS found for C₂₀H₂₁F₂N₅OS m/z 418.1(M+1).

1-(2,2-Difluoropropyl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide28.

Beige solid (3.0 mg, 0.007 mmol, 4.9% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.63 (3H, t, J=19.07 Hz), 1.67-1.75 (2H, m), 1.75-1.81 (2H, m),2.22 (2H, td, J=11.73, 2.33 Hz), 2.52-2.60 (1H, m), 2.71 (2H, t, J=14.00Hz), 2.83 (3H, s), 2.92-2.99 (2H, m), 8.09 (1H, dd, J=8.51, 1.65 Hz),8.19 (1H, d, J=8.78 Hz), 8.45 (1H, d, J=0.82 Hz), 8.62 (1H, s), 9.21(1H, s), 10.64 (1H, s); ESIMS found for C₂₁H₂₃F₂N₅OS m/z 432.2 (M+1).

1-Methyl-3-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(1-methylpiperidin-4-yl)urea29.

Beige solid (70.0 mg, 0.177 mmol, 10.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.58 (2H, br d, J=10.98 Hz), 1.73-1.85 (2H, m), 2.18 (2H,br s), 2.29 (3H, br s), 2.82 (3H, s), 2.89 (3H, s), 2.91-3.01 (2H, m),4.10-4.20 (1H, m), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.78Hz), 8.32 (1H, s), 8.36 (1H, s), 9.00 (1H, s), 9.16 (1H, s); ESIMS foundfor C₂₀H₂₄N₆OS m/z 397.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-(methylamino)piperidine-1-carboxamide 30.

Beige solid (310.0 mg, 0.811 mmol, 96.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.13-1.22 (2H, m), 1.77-1.86 (2H, m), 2.28 (3H, s),2.43-2.49 (1H, m), 2.82 (3H, s), 2.92-3.02 (2H, m), 4.06 (2H, dt,J=13.45, 3.43 Hz), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.14 (1H, d, J=8.51Hz), 8.30 (1H, s), 8.37 (1H, d, J=0.82 Hz), 9.15 (1H, s), 9.27 (1H, s);ESIMS found for C₁₉H₂₂N₆OS m/z 383.2 (M+1).

4-(Dimethylamino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 31.

Off-white solid (55.0 mg, 0.139 mmol, 33.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.32 (2H, qd, J=11.98, 3.84 Hz), 1.77 (2H, br d, J=10.70Hz), 2.18 (6H, s), 2.29 (1H, tt, J=10.91, 3.50 Hz), 2.79-2.89 (2H, m),2.82 (3H, s), 4.22 (2H, br d, J=13.17 Hz), 8.02 (1H, dd, J=8.64, 1.78Hz), 8.15 (1H, d, J=8.51 Hz), 8.30 (1H, s), 8.37 (1H, d, J=0.82 Hz),9.15 (1H, s), 9.31 (1H, s); ESIMS found for C₂₀H₂₄N₆OS m/z 397.2 (M+1).

4-((2,2-Difluoroethyl)(methyl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 32.

Beige solid (25.0 mg, 0.056 mmol, 21.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.55 (2H, br d, J=11.25 Hz), 1.75 (2H, qd, J=12.17, 3.84Hz), 2.26-2.34 (2H, m), 2.74 (2H, td, J=15.64, 4.39 Hz), 2.82 (3H, s),2.89 (3H, s), 2.98 (2H, br d, J=11.53 Hz), 4.07-4.18 (1H, m), 6.13 (1H,tt, J=55.80, 4.40 Hz), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d,J=8.51 Hz), 8.33 (1H, s), 8.36 (1H, s), 9.00 (1H, s), 9.16 (1H, s);ESIMS found for C₂₁H₂₄F₂N₆OS m/z 447.2 (M+1).

(3S,4S)-4-Amino-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide33.

Beige solid (38.0 mg, 0.098 mmol, 95.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.28-1.39 (1H, m), 1.84 (2H, dt, J=13.10, 4.01 Hz), 2.82(3H, s), 2.85-2.94 (1H, m), 3.10-3.24 (2H, m), 3.84-3.94 (1H, m),4.11-4.29 (2H, m), 8.03 (1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d, J=8.51Hz), 8.30 (1H, s), 8.39 (1H, s), 9.17 (1H, s), 9.45 (1H, s); ESIMS foundfor C₁₈H₁₉FN₆OS m/z 387.1 (M+1).

(3S,4S)-4-(Dimethylamino)-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 34.

Off-white solid (25.0 mg, 0.060 mmol, 66.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.41-1.54 (1H, m), 1.74-1.84 (1H, m), 2.28 (6H, s), 2.64(1H, tdd, J=10.94, 10.94, 8.71, 4.53 Hz), 2.82 (3H, s), 2.93-3.02 (1H,m), 3.05 (1H, ddd, J=12.97, 9.13, 5.63 Hz), 4.00-4.11 (1H, m), 4.25-4.35(1H, m), 4.63 (1H, dsxt, J=49.00, 4.10, 4.10, 4.10, 4.10, 4.10 Hz), 8.03(1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d, J=8.78 Hz), 8.30 (1H, s), 8.39(1H, d, J=0.82 Hz), 9.17 (1H, s), 9.48 (1H, s); ESIMS found forC₂₀H₂₃FN₆OS m/z 415.2 (M+1).

(3S,4S)-3-Fluoro-4-(isopropylamino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 35.

Off-white solid (40.0 mg, 0.093 mmol, 56.4% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.98 (3H, d, J=6.31 Hz), 1.01 (3H, d, J=6.04 Hz),1.25-1.38 (1H, m), 1.86-1.95 (1H, m), 2.82 (3H, s), 2.86-2.97 (2H, m),3.22-3.29 (1H, m), 3.34-3.44 (1H, m), 3.75-3.83 (1H, m), 4.04 (1H, ddd,J=17.91, 14.07, 3.43 Hz), 4.25-4.42 (1H, m), 8.03 (1H, dd, J=8.51, 1.65Hz), 8.16 (1H, d, J=8.51 Hz), 8.29 (1H, s), 8.39 (1H, s), 9.17 (1H, s),9.43 (1H, s); ESIMS found for C₂₁H₂₅FN₆OS m/z 429.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)morpholine-4-carboxamide36.

Beige solid (30.0 mg, 0.084 mmol, 20.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.82 (3H, s), 3.48-3.54 (4H, m), 3.59-3.66 (4H, m), 8.03(1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d, J=8.78 Hz), 8.32 (1H, s), 8.39(1H, s), 9.17 (1H, s), 9.37 (1H, s); ESIMS found for C₁₇H₁₇N₅O₂S m/z356.1 (M+1).

trans-4-(Methyl(oxetan-3-yl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide37.

White solid (6.0 mg, 0.014 mmol, 8.7% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.16-1.30 (2H, m), 1.47 (2H, qd, J=12.72, 2.74 Hz), 1.68 (2H, brd, J=10.15 Hz), 1.85-1.94 (2H, m), 2.12 (3H, s), 2.30 (1H, tt, J=11.53,3.02 Hz), 2.41-2.48 (1H, m), 2.53 (3H, s), 3.90 (1H, quin, J=6.86 Hz),4.43-4.53 (4H, m), 7.78 (1H, s), 7.80 (1H, dd, J=8.64, 1.51 Hz),8.05-8.12 (2H, m), 8.49 (1H, s), 9.10 (1H, s), 10.50 (1H, s); ESIMSfound for C₂₄H₂₈N₄O₃ m/z 421.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-(3,3,3-trifluoropropyl)piperidine-4-carboxamide38.

White solid (150.0 mg, 0.334 mmol, 41.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.73 (2H, m), 1.81 (2H, br d, J=10.98 Hz), 1.93-2.01(2H, m), 2.41-2.61 (5H, m), 2.83 (3H, s), 2.94 (2H, br d, J=11.53 Hz),8.09 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51 Hz), 8.44 (1H, s),8.62 (1H, s), 9.21 (1H, s), 10.64 (1H, s); ESIMS found for C₂₁H₂₂F₃N₅OSm/z 450.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholino-d₈)acetamide 39.

White solid (65.0 mg, 0.181 mmol, 64.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.24 (2H, s), 3.90 (3H, s), 7.77 (1H, dd, J=8.51, 1.65Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s), 8.37 (1H, s), 8.44 (1H, s),9.04 (1H, s), 10.00 (1H, s); ESIMS found for C₁₉H₁₃[²H₈]N₅O₂ m/z 360.2(M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(morpholino-d₈)acetamide40.

Off-white solid (72.0 mg, 0.200 mmol, 71.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.53 (3H, s), 3.25 (2H, s), 7.80 (1H, s), 7.84 (1H, dd,J=8.51, 1.65 Hz), 8.12 (1H, d, J=8.78 Hz), 8.16 (1H, s), 8.51 (1H, s),9.13 (1H, s), 10.08 (1H, s); ESIMS found for C₁₉H₁₂[²H₈]N₄O₃ m/z 361.2(M+1).

N-(6-(2-Methylthiazol-5-yl)isoquinolin-3-yl)-2-(morpholino-d₈)acetamide41.

White solid (12.0 mg, 0.032 mmol, 11.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.72 (3H, s), 3.25 (2H, s), 7.82 (1H, dd, J=8.51, 1.65Hz), 8.10 (1H, d, J=8.51 Hz), 8.15 (1H, s), 8.30 (1H, s), 8.50 (1H, s),9.12 (1H, s), 10.08 (1H, s); ESIMS found for C₁₉H₁₂[²H₈]N₄O₂S m/z 377.2M+1).

(S)-2,4-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide 42.

Yellow solid (7.0 mg, 0.019 mmol, 4.3% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.22 (3H, d, J=6.59 Hz), 1.85 (1H, td, J=11.66, 3.29 Hz), 2.04(1H, dd, J=11.11, 3.70 Hz), 2.17 (3H, s), 2.63 (1H, br d, J=10.98 Hz),2.72-2.79 (1H, m), 3.10 (1H, td, J=12.62, 3.29 Hz), 3.90 (3H, s), 3.95(1H, br d, J=13.17 Hz), 4.38-4.46 (1H, m), 7.68 (1H, dd, J=8.37, 1.51Hz), 7.96 (1H, d, J=8.51 Hz), 7.98 (1H, s), 8.06 (1H, s), 8.14 (1H, s),8.33 (1H, s), 8.97 (1H, s), 9.01 (1H, s); ESIMS found for C₂₀H₂₄N₆O m/z365.2 (M+1).

trans-4-(Hydroxymethyl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 43.

White solid (355.0 mg, 0.972 mmol, 49.1% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.95 (2H, qd, J=12.76, 2.88 Hz), 1.31-1.40 (1H, m), 1.45(2H, qd, J=12.67, 3.43 Hz), 1.80 (2H, br dd, J=13.17, 2.47 Hz), 1.88(2H, br dd, J=13.04, 2.61 Hz), 2.42-2.48 (1 H, m), 2.53 (3H, s), 3.24(2H, t, J=5.76 Hz), 4.39 (1H, t, J=5.35 Hz), 7.79 (1H, s), 7.79-7.84(1H, m), 8.09 (1H, s), 8.10 (1H, d, J=6.04 Hz), 8.50 (1H, s), 9.10 (1H,s), 10.49 (1H, s); ESIMS found for C₂₁H₂₃N₃O₃ m/z 366.2 (M+1).

trans-4-((2,2-Difluoroethyl)(methyl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 44.

White solid (35.0 mg, 0.082 mmol, 62.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.24 (2H, qd, J=12.44, 3.29 Hz), 1.49 (2H, qd, J=12.67,2.88 Hz), 1.80 (2H, br d, J=10.15 Hz), 1.92 (2H, br d, J=11.80 Hz), 2.30(3H, s), 2.39-2.48 (2H, m), 2.53 (3H, s), 2.77 (2H, td, J=15.51, 4.39Hz), 6.00 (1H, tt, J=56.40, 4.10 Hz), 7.78 (1H, s), 7.79-7.84 (1H, m),8.07-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.51 (1H, s); ESIMSfound for C₂₃H₂₆F₂N₄O₂ m/z 429.2 (M+1).

trans-4-(Dimethylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 45.

Beige solid (92.0 mg, 0.243 mmol, 45.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.13-1.23 (2H, m), 1.42-1.53 (2H, m), 1.82-1.95 (4H, m),2.10-2.16 (1H, m), 2.18 (6H, s), 2.43-2.49 (1H, m), 2.53 (3H, s), 7.78(1H, s), 7.79-7.84 (1H, m), 8.05-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H,s), 10.49 (1H, s); ESIMS found for C₂₂H₂₆N₄O₂ m/z 379.2 (M+1).

1-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-4-carboxamide46.

Beige solid (102.0 mg, 0.278 mmol, 33.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.61-1.73 (2H, m), 1.75-1.81 (2H, m), 1.83-1.92 (2H, m),2.16 (3H, s), 2.51-2.56 (1H, m), 2.77-2.87 (2H, m), 2.83 (3H, s), 8.09(1H, dd, J=8.51, 1.37 Hz), 8.19 (1H, d, J=8.51 Hz), 8.44 (1H, s), 8.62(1H, s), 9.21 (1H, s), 10.63 (1H, s); ESIMS found for C₁₉H₂₁N₅OS m/z368.15 (M+1).

1-Methyl-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)piperidine-4-carboxamide47.

Beige solid (240.0 mg, 0.685 mmol, 77.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.61-1.73 (2H, m), 1.74-1.81 (2H, m), 1.86 (2H, td,J=11.66, 2.47 Hz), 2.16 (3H, s), 2.46-2.52 (1H, m), 2.53 (3H, s),2.77-2.85 (2H, m), 7.78 (1H, s), 7.81 (1H, dd, J=8.64, 1.51 Hz),8.05-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.54 (1H, s); ESIMSfound for C₂₀H₂₂N₄O₂ m/z 351.2 (M+1).

2-(4-Methoxypiperidin-1-yl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)acetamide 48.

White solid (45.0 mg, 0.118 mmol, 44.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.46-1.58 (2H, m), 1.83-1.93 (2H, m), 2.32-2.41 (2H, m),2.53 (3H, s), 2.73-2.82 (2H, m), 3.21 (2H, s), 3.22-3.24 (1H, m), 3.24(3H, s), 7.80 (1H, s), 7.83 (1H, dd, J=8.64, 1.51 Hz), 8.12 (1H, d,J=8.51 Hz), 8.16 (1H, s), 8.50 (1H, s), 9.12 (1H, s), 10.01 (1H, s);ESIMS found for C₂₁H₂₄N₄O₃ m/z 381.2 (M+1).

2-(4-Methoxypiperidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)acetamide 49.

Beige solid (50.0 mg, 0.126 mmol, 23.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.47-1.57 (2H, m), 1.84-1.92 (2H, m), 2.34-2.42 (2H, m),2.73-2.81 (2H, m), 2.83 (3H, s), 3.20-3.26 (1H, m), 3.23 (2H, s), 3.24(3H, s), 8.12 (1H, dd, J=8.64, 1.78 Hz), 8.21 (1H, d, J=8.51 Hz), 8.50(1H, d, J=0.82 Hz), 8.61 (1H, s), 9.23 (1H, s), 10.10 (1H, s); ESIMSfound for C₂₀H₂₃N₅O₂S m/z 398.2 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinopiperidine-1-carboxamide50.

Off-white solid (25.0 mg, 0.059 mmol, 13.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.27-1.41 (2H, m), 1.76-1.84 (2H, m), 2.36 (1H, tt,J=10.94, 3.60 Hz), 2.44-2.49 (4H, m), 2.53 (3H, s), 2.83 (2H, brt,J=11.66 Hz), 3.52-3.60 (4H, m), 4.17-4.27 (2H, m), 7.74 (1H, dd, J=8.51,1.65 Hz), 7.76 (1H, s), 8.04 (1H, s), 8.06 (1H, d, J=8.51 Hz), 8.19 (1H,s), 9.05 (1H, s), 9.20 (1H, s); ESIMS found for C₂₃H₂₇N₅O₃ m/z 422.2(M+1).

(3S,4S)-4-Amino-3-fluoro-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)piperidine-1-carboxamide 51.

Off-white solid (55.0 mg, 0.149 mmol, 61.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.27-1.38 (1H, m), 1.77-1.88 (1H, m), 2.00 (2H, br s),2.53 (3H, s), 2.83-2.94 (1H, m), 3.07-3.22 (2H, m), 3.85-3.95 (1H, m),4.11-4.29 (2H, m), 7.75 (1H, dd, J=8.64, 1.78 Hz), 7.77 (1H, s), 8.05(1H, s), 8.07 (1H, d, J=8.51 Hz), 8.19 (1H, s), 9.06 (1H, s), 9.37 (1H,s); ESIMS found for C₁₉H₂₀FN₅O₂ m/z 370.2 (M+1).

4-((2,2-Difluoroethyl)(methyl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)piperidine-1-carboxamide 52.

Beige solid (35.0 mg, 0.082 mmol, 18.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.29-1.41 (2H, m), 1.71 (2H, br dd, J=12.35, 1.37 Hz),2.30 (3H, s), 2.53 (3H, s), 2.58-2.67 (2H, m), 2.73-2.85 (4H, m), 4.27(2H, br d, J=13.72 Hz), 6.01 (1H, tt, J=56.10, 4.40 Hz), 7.74 (1H, dd,J=8.51, 1.65 Hz), 7.76 (1H, s), 8.04 (1H, s), 8.06 (1H, d, J=8.51 Hz),8.20 (1H, s), 9.05 (1H, s), 9.20 (1H, s); ESIMS found for C₂₂H₂₅F₂N₅O₂m/z 430.2 (M+1).

(3 S,4S)-3-Fluoro-4-(isopropylamino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)piperidine-1-carboxamide 53.

Off-white solid (17.0 mg, 0.041 mmol, 47.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.98 (3H, d, J=6.04 Hz), 1.01 (3H, d, J=6.31 Hz),1.26-1.37 (1H, m), 1.55 (1H, br s), 1.85-1.95 (1H, m), 2.53 (3H, s),2.83-2.97 (2H, m), 3.24 (1H, ddd, J=13.24, 9.67, 3.16 Hz), 3.35-3.40(1H, m), 3.74-3.83 (1H, m), 3.98-4.10 (1H, m), 4.33 (1H, dsxt, J=48.10,3.60, 3.60, 3.60, 3.60, 3.60 Hz), 7.75 (1H, dd, J=8.64, 1.51 Hz), 7.77(1H, s), 8.05 (1H, br s), 8.06 (1H, d, J=8.51 Hz), 8.19 (1H, s), 9.06(1H, s), 9.32 (1H, s); ESIMS found for C₂₂H₂₆FN₅O₂ m/z 412.2 (M+1).

2-(4-Methoxypiperidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)acetamide 54.

White solid (60.0 mg, 0.158 mmol, 23.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.47-1.58 (2H, m), 1.89 (2H, br dd, J=9.19, 3.98 Hz),2.32-2.41 (2H, m), 2.74-2.82 (2H, m), 3.20-3.27 (1H, m), 3.22 (2H, s),3.24 (3H, s), 4.14 (3H, s), 8.04 (1H, dd, J=8.51, 1.65 Hz), 8.13 (1H, d,J=8.51 Hz), 8.33 (1H, s), 8.50 (1H, s), 8.74 (1H, s), 9.13 (1H, s),10.01 (1H, s); ESIMS found for C₂₀H₂₄N₆O₂ m/z 381.2 (M+1).

trans-N-(7-Fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide55.

Beige solid (98.0 mg, 0.224 mmol, 82.3% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.17-1.28 (2H, m), 1.43-1.54 (2H, m), 1.86-1.96 (4H, m),2.16-2.26 (1H, m), 2.44-2.49 (5H, m), 2.56 (3H, s), 3.53-3.61 (4H, m),7.60 (1H, d, J=4.39 Hz), 8.01 (1H, d, J=11.53 Hz), 8.23 (1H, d, J=6.86Hz), 8.56 (1H, s), 9.10 (1H, s), 10.54 (1H, s); ESIMS found forC₂₄H₂₇FN₄O₃ m/z 439.2 (M+1).

trans-N-(8-Fluoro-6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide56.

Off-white solid (54.0 mg, 0.123 mmol, 36.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.16-1.31 (2H, m), 1.42-1.54 (2H, m), 1.86-1.99 (4H, m),2.17-2.27 (1H, m), 2.48 (4H, br s), 2.52-2.55 (1H, m), 3.56 (4H, br s),4.14 (3H, s), 7.77 (1H, dd, J=11.53, 1.10 Hz), 8.16 (1H, s), 8.56 (1H,s), 8.76 (1H, s), 9.24 (1H, s), 10.66 (1H, s); ESIMS found forC₂₃H₂₇FN₆O₂ m/z 439.2 (M+1).

trans-N-(8-Fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide57.

Off-white solid (46.0 mg, 0.155 mmol, 29.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.17-1.30 (2H, m), 1.42-1.55 (2H, m), 1.86-1.99 (4H, m),2.17-2.27 (1H, m), 2.48 (4H, br s), 2.51-2.56 (1H, m), 2.83 (3H, s),3.52-3.62 (4H, m), 7.85 (1H, dd, J=11.11, 1.24 Hz), 8.34 (1H, s), 8.68(1H, s), 9.32 (1H, s), 10.75 (1H, s); ESIMS found for C₂₃H₂₆FN₅O₂S m/z456.2 (M+1).

2-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxamide58.

Beige solid (55.0 mg, 0.136 mmol, 32.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.07 (3H, s), 2.82 (3H, s), 3.91-3.97 (2H, m), 3.97-4.03(2H, m), 4.68 (2H, s), 6.79 (1H, s), 8.05 (1H, dd, J=8.51, 1.65 Hz),8.17 (1H, d, J=8.78 Hz), 8.33 (1H, s), 8.40 (1H, s), 9.19 (1H, s), 9.71(1H, s); ESIMS found for C₂₀H₁₉N₇OS m/z 406.15 (M+1).

2-Methyl-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxamide 59.

White solid (61.0 mg, 0.157 mmol, 35.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.07 (3H, d, J=0.82 Hz), 2.53 (3H, s), 3.89-3.96 (2H, m),3.96-4.02 (1H, m), 4.67 (2H, s), 6.78 (1H, d, J=0.82 Hz), 7.77 (1H, dd,J=8.51, 1.65 Hz), 7.77 (1H, s), 8.06 (1H, s), 8.08 (1H, d, J=8.51 Hz),8.22 (1H, s), 9.09 (1H, s), 9.61 (1H, s); ESIMS found for C₂₁H₂₀N₆O₂ m/z389.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)morpholine-4-carboxamide60.

Beige solid (40.0 mg, 0.118 mmol, 26.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.49-3.54 (4H, m), 3.60-3.65 (4H, m), 4.14 (3H, s), 7.95(1H, dd, J=8.51, 1.65 Hz), 8.08 (1H, d, J=8.51 Hz), 8.21 (1H, s), 8.23(1H, s), 8.71 (1H, s), 9.07 (1H, s), 9.25 (1H, s); ESIMS found forC₁₇H₁₈N₆O₂ m/z 339.15 (M+1).

3-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide61.

Yellow solid (25.0 mg, 0.066 mmol, 14.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.73-1.86 (4H, m), 2.15 (3H, s), 2.16 (2H, br d, J=11.25Hz), 2.61 (2H, dd, J=10.84, 2.33 Hz), 3.90 (3H, s), 4.48 (2H, br s),7.68 (1H, dd, J=8.37, 1.51 Hz), 7.96 (1H, d, J=8.51 Hz), 7.98 (1H, s),8.06 (1H, s), 8.22 (1H, s), 8.33 (1H, s), 8.97 (1H, s), 9.14 (1H, s);ESIMS found for C₂₁H₂₄N₆O m/z 377.2 (M+1).

4-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperazine-1-carboxamide62.

Beige solid (20.0 mg, 0.054 mmol, 6.6% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.20 (3H, s), 2.29-2.35 (4H, m), 2.82 (3H, s), 3.49-3.56 (4H, m),8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.78 Hz), 8.31 (1H, s),8.38 (1H, s), 9.16 (1H, s), 9.33 (1H, s); ESIMS found for C₁₈H₂₀N₆OS m/z369.1 (M+1).

4-(Dimethylamino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-1-carboxamide 63.

Beige solid (20.0 mg, 0.053 mmol, 5.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.31 (2H, qd, J=11.98, 3.84 Hz), 1.76 (2H, br d, J=10.98 Hz), 2.18(6H, s), 2.24-2.34 (1H, m), 2.78-2.87 (2H, m), 3.90 (3H, s), 4.21 (2H,br d, J=13.17 Hz), 7.67 (1H, dd, J=8.51, 1.65 Hz), 7.93-7.99 (2H, m),8.06 (1H, s), 8.14 (1H, s), 8.33 (1H, s), 8.97 (1H, s), 9.10 (1H, s);ESIMS found for C₂₁H₂₆N₆O m/z 379.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)morpholine-4-carboxamide64.

Beige solid (25.0 mg, 0.074 mmol, 15.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.47-3.54 (4H, m), 3.58-3.65 (4H, m), 3.90 (3H, s), 7.69(1H, dd, J=8.51, 1.65 Hz), 7.94-8.00 (2H, m), 8.07 (1H, s), 8.15 (1H,s), 8.33 (1H, s), 8.98 (1H, s), 9.17 (1H, s); ESIMS found for C₁₈H₁₉N₅O₂m/z 338.2 (M+1).

4-isopropyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide65.

Beige solid (2.0 mg, 0.005 mmol, 0.6% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.98 (6H, d, J=6.59 Hz), 2.43-2.47 (4H, m), 2.65-2.72 (1H, m),3.46-3.52 (4H, m), 3.90 (3H, s), 7.68 (1H, dd, J=8.51, 1.65 Hz),7.94-7.99 (2H, m), 8.06 (1H, s), 8.14 (1H, s), 8.33 (1H, s), 8.97 (1H,s), 9.09 (1H, s); ESIMS found for C₂₁H₂₆N₆O m/z 379.2 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide66.

White solid (32.0 mg, 0.091 mmol, 51.2% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.61-1.73 (2H, m), 1.74-1.80 (2H, m), 1.86 (2H, td,J=11.66, 2.47 Hz), 2.16 (3H, s), 2.45-2.53 (1H, m), 2.77-2.84 (2H, m),3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, d, J=8.51 Hz),8.02-8.04 (1H, m), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 9.02 (1H, s),10.46 (1H, s); ESIMS found for C₂₀H₂₂[²H]N₅O m/z 351.2 (M+1).

(R)-3,4-Dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperazine-1-carboxamide 67.

Beige solid (26.0 mg, 0.071 mmol, % yield). ¹H NMR (499 MHz, DMSO-d₆) δppm 1.01 (3H, d, J=6.31 Hz), 1.99 (1H, br s), 2.04-2.12 (1H, m), 2.19(3H, s), 2.61 (1H, dd, J=12.76, 10.29 Hz), 2.74 (1H, br d, J=11.53 Hz),2.93-3.02 (1H, m), 3.90 (3H, s), 3.99-4.10 (2H, m), 7.65-7.71 (1H, m),7.93-7.99 (2H, m), 8.06 (1H, s), 8.14 (1H, s), 8.33 (1H, s), 8.97 (1H,s), 9.13 (1H, s); ESIMS found for C₂₀H₂₄N₆O m/z 365.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-4-d)-2-morpholinoacetamide68.

Beige solid (4.0 mg, 0.011 mmol, 3.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.55-2.61 (4H, m), 3.24 (2H, s), 3.62-3.69 (4H, m), 3.90 (3H, s),7.77 (1H, dd, J=8.51, 1.37 Hz), 8.02 (1H, d, J=8.51 Hz), 8.10 (2H, s),8.37 (1H, s), 9.04 (1H, s), 10.00 (1H, s); ESIMS found forC₁₉H₂₀[²H]N₅O₂ m/z 352.2 (M+1).

trans-N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-4-(morpholinomethyl)cyclohexane-1-carboxamide 69.

Off-white solid (21.0 mg, 0.048 mmol, 17.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.81-0.94 (2H, m), 1.41-1.56 (3H, m), 1.80-1.91 (4H, m),2.09 (2H, d, J=7.41 Hz), 2.31 (4H, br s), 2.51-2.56 (1H, m), 2.53 (3H,s), 3.56 (4H, t, J=4.53 Hz), 7.78 (1H, s), 7.79-7.84 (1H, m), 8.05-8.11(2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.49 (1H, s); ESIMS found forC₂₅H₃₀N₄O₃ m/z 435.2 (M+1).

trans-N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)cyclohexane-1-carboxamide70.

White solid (38.0 mg, 0.085 mmol, 28.1% yield). H NMR (499 MHz, DMSO-d₆)δ ppm 0.83-0.94 (2H, m), 1.40-1.54 (3H, m), 1.79-1.90 (4H, m), 2.08 (2H,d, J=7.41 Hz), 2.14 (3H, s), 2.31 (8H, br s), 2.52 (1H, br s), 2.53 (3H,s), 7.78 (1H, s), 7.79-7.84 (1H, m), 8.06-8.12 (2H, m), 8.50 (1H, s),9.10 (1H, s), 10.48 (1H, s); ESIMS found for C₂₆H₃₃N₅O₂ m/z 448.25(M+1).

1-((3S,4S)-3-Fluoro-1-methylpiperidin-4-yl)-3-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)urea71.

Pale yellow solid (40.0 mg, 0.100 mmol, 64.3% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.46-1.56 (1H, m), 1.91-2.00 (1H, m), 2.06-2.13 (1H, m),2.14-2.20 (1H, m), 2.23 (3H, s), 2.56-2.62 (1H, m), 2.82 (3H, s),2.91-3.01 (1H, m), 3.67-3.78 (1H, m), 4.37-4.54 (1H, m), 7.25 (1H, br d,J=7.68 Hz), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.14 (1H, d, J=8.78 Hz),8.19 (1H, s), 8.35 (1H, s), 9.13 (1H, s), 9.15 (1H, s); ESIMS found forC₁₉H₂₁FN₆OS m/z 401.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl-d₁₀)isonicotinamide72.

Beige solid (72.0 mg, 0.175 mmol, 74.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.09 (1H, dd, J=5.21, 1.37Hz), 7.14 (1H, s), 7.43 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 8.00(1H, s), 8.14 (1H, d, J=8.51 Hz), 8.23 (1H, d, J=5.21 Hz), 8.67 (1H, s),9.22 (1H, s), 11.08 (1H, s); ESIMS found for C₂₅H₁₆[²H¹⁰]N₆O m/z 437.25(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-2,2,5,5-d₄)isonicotinamide73.

Beige solid (48.0 mg, 0.115 mmol, 52.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.96 (4H, s), 2.40 (3H, s), 3.68 (3H, s), 7.06 (1H, dd,J=5.08, 1.51 Hz), 7.08 (1H, d, J=0.82 Hz), 7.14 (1H, s), 7.67 (1H, dd,J=8.51, 1.37 Hz), 8.00 (1H, s), 8.14 (1H, d, J=8.78 Hz), 8.20 (1H, d,J=4.94 Hz), 8.67 (1H, s), 9.21 (1H, s), 11.03 (1H, s); ESIMS found forC₂₄H₂₀[²H₄]N₆O m/z 417.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(morpholino-d₈)isonicotinamide 74.

Beige solid (30.0 mg, 0.069 mmol, 59.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.14 (1H, s), 7.20 (1H, dd,J=4.94, 1.37 Hz), 7.47 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 8.00(1H, s), 8.15 (1H, d, J=8.78 Hz), 8.28 (1H, d, J=5.21 Hz), 8.68 (1H, s),9.22 (1H, s), 11.10 (1H, s); ESIMS found for C₂₄H₁₆[²H₈]N₆O₂ m/z 437.25(M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl-d₁₀)isonicotinamide 75.

Beige solid (68.0 mg, 0.161 mmol, 69.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.06-7.11 (1H, m), 7.33 (1H, d, J=1.10 Hz),7.42-7.47 (1H, m), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10(1H, d, J=0.82 Hz), 8.15 (1H, d, J=8.78 Hz), 8.23 (1H, d, J=5.76 Hz),8.69 (1H, s), 9.22 (1H, s), 11.10 (1H, s); ESIMS found forC₂₄H₁₄[²H¹⁰]N₆O m/z 423.3 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(morpholino-d₈)isonicotinamide 76.

Beige solid (20.0 mg, 0.047 mmol, 20.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.20 (1H, dd, J=5.08, 1.24 Hz), 7.34 (1H,br s), 7.47 (1H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.82 (1H, br s),8.10 (1H, s), 8.15 (1H, d, J=8.51 Hz), 8.28 (1H, d, J=5.21 Hz), 8.70(1H, s), 9.23 (1H, s), 11.11 (1H, s); ESIMS found for C₂₃H₁₄[²H₈]N₆O₂m/z 423.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-d₈)isonicotinamide77.

Beige solid (19.0 mg, 0.045 mmol, 38.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.06 (1H, dd, J=5.08, 1.51Hz), 7.08 (1H, s), 7.14 (1H, s), 7.67 (1H, dd, J=8.37, 1.51 Hz), 8.00(1H, s), 8.14 (1H, d, J=8.51 Hz), 8.20 (1H, d, J=5.21 Hz), 8.67 (1H, s),9.21 (1H, s), 11.03 (1H, s); ESIMS found for C₂₄H₁₆[²H₈]N₆O m/z 421.25(M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-d₈)isonicotinamide 78.

White solid (68.0 mg, 0.167 mmol, 72.3% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.06 (1H, dd, J=5.21, 1.37 Hz), 7.07-7.13(1H, m), 7.33 (1H, d, J=1.10 Hz), 7.74 (1H, dd, J=8.51, 1.92 Hz), 7.81(1H, s), 8.10 (1H, d, J=0.82 Hz), 8.15 (1H, d, J=8.78 Hz), 8.20 (1H, dd,J=5.21, 0.82 Hz), 8.69 (1H, s), 9.22 (1H, s), 11.05 (1H, s); ESIMS foundfor C₂₃H₁₄[²H₈]N₆O m/z 407.3 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl-2,2,5,5-d₄)isonicotinamide79.

Beige solid (58.0 mg, 0.144 mmol, 62.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.96 (4H, s), 3.85 (3H, s), 7.06 (1H, dd, J=5.21, 1.37Hz), 7.07-7.12 (1H, m), 7.33 (1H, d, J=1.10 Hz), 7.74 (1H, dd, J=8.51,1.65 Hz), 7.81 (1H, s), 8.10 (1H, d, J=0.82 Hz), 8.15 (1H, d, J=8.78Hz), 8.18-8.24 (1H, m), 8.69 (1H, s), 9.22 (1H, s), 11.05 (1H, s); ESIMSfound for C₂₃H₁₈[²H₄]N₆O m/z 403.15 (M+1).

2-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄80.

Off-white solid (15.4 mg, 0.044 mmol, 49.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.86 (3H, s), 7.33 (1H, s), 7.73 (1H, dd, J=8.51, 1.65Hz), 7.81 (1H, s), 8.11 (1H, s), 8.14 (1H, d, J=8.51 Hz), 8.68 (1H, s),9.18 (1H, s); ESIMS found for C₂₀H¹¹[²H₄]FN₄O m/z 351.2 (M+1).

4-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄81.

Off-white solid (15.1 mg, 0.043 mmol, 34.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.33 (1H, d, J=0.82 Hz), 7.73 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1 H, s), 8.09 (1H, s), 8.14 (1H, d, J=8.51 Hz),8.69 (1H, s), 9.22 (1H, s), 10.95 (1H, s); ESIMS found forC₂₀H₁₁[²H₄]FN₄O m/z 351.15 (M+1).

2-Chloro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄82.

Off-white solid (9.8 mg, 0.027 mmol, 30.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.86 (3H, s), 7.33 (1H, s), 7.73 (1H, dd, J=8.37, 1.78Hz), 7.81 (1H, s), 8.09-8.17 (2H, m), 8.68 (1H, s), 9.17 (1H, s), 11.14(1H, s); ESIMS found for C₂₀H₁₁[²H₄]ClN₄O m/z 367.1 (M+1).

4-Chloro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄83.

Off-white solid (16.0 mg, 0.044 mmol, 34.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.33 (1H, d, J=0.82 Hz), 7.73 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, s), 8.14 (1H, d, J=8.51 Hz),8.69 (1H, s), 9.22 (1H, s), 11.02 (1H, s); ESIMS found forC₂₀H₁₁[²H₄]ClN₄O m/z 367.1 (M+1).

4-(Methyl-d₃)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide84.

Off-white solid (9.0 mg, 0.026 mmol, 29.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.31-7.37 (3H, m), 7.72 (1H, dd, J=8.51,1.65 Hz), 7.81 (1H, s), 7.98-8.03 (2H, m), 8.08 (1H, s), 8.14 (1H, d,J=8.51 Hz), 8.69 (1H, s), 9.21 (1H, s), 10.79 (1H, s); ESIMS found forC₂₁H₁₅[²H₃]N₄O m/z 346.2 (M+1).

4-Methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄85.

Off-white solid (6.9 mg, 0.020 mmol, 22.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.85 (3H, s), 7.33 (1H, s), 7.72 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1H, s), 8.08 (1H, s), 8.14 (1H, d, J=8.51 Hz),8.69 (1H, s), 9.21 (1H, s), 10.79 (1H, s); ESIMS found forC₂₁H₁₄[²H₄]N₄O m/z 347.2 (M+1).

4-(Methyl-d₃)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄ 86.

Off-white solid (15.5 mg, 0.044 mmol, 35.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.33 (1H, d, J=0.82 Hz), 7.72 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1H, s), 8.08 (1H, d, J=0.82 Hz), 8.14 (1H, d,J=8.51 Hz), 8.69 (1H, s), 9.21 (1H, s), 10.79 (1H, s); ESIMS found forC₂₁H₁₁[²H₇]N₄O m/z 350.2 (M+1).

4-(Methoxy-d₃)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide 87.

Off-white solid (13.7 mg, 0.038 mmol, 42.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.02-7.10 (2H, m), 7.32 (1H, s), 7.71 (1H,dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.07 (1H, s), 8.08-8.12 (2H, m),8.13 (1H, d, J=8.51 Hz), 8.68 (1H, s), 9.20 (1H, s), 10.72 (1H, s);ESIMS found for C₂₁H₁₅[²H₃]N₄O₂ m/z 362.1 (M+1).

4-(Methoxy-d₃)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄ 88.

Off-white solid (8.4 mg, 0.023 mmol, 18.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.33 (1H, br s), 7.71 (1H, dd, J=8.51, 1.65Hz), 7.81 (1H, s), 8.07 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.68 (1H, s),9.20 (1H, s), 10.72 (1H, s); ESIMS found for C₂₁H₁₁[²H₇]N₄O₂ m/z 366.2(M+1).

4-Methoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄89.

Off-white solid (8.1 mg, 0.022 mmol, 25.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (6H, s), 7.33 (1H, s), 7.71 (1H, dd, J=8.51, 1.65Hz), 7.81 (1H, s), 8.07 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.68 (1H, s),9.20 (1H, s), 10.72 (1H, s); ESIMS found for C₂₁H₁₄[²H₄]N₄O₂ m/z 363.2(M+1).

(E)-N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-(phenyl-2,3,4,5,6-d₅)acrylamide90.

Brown solid (6.5 mg, 0.017 mmol, 13.8% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.13 (1H, br d, J=15.64 Hz), 7.14 (1H,s), 7.63 (1H, dd, J=8.51, 1.65 Hz), 7.66 (1H, d, J=15.64 Hz), 7.96 (1H,s), 8.11 (1H, d, J=8.51 Hz), 8.67 (1H, s), 9.16 (1H, s), 10.83 (1H, s);ESIMS found for C₂₃H₁₅[²H₅]N₄O m/z 374.2 (M+1).

(E)-N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-(phenyl-2,3,4,5,6-d₅)acrylamide-2,3-d₂91.

Brown solid (5.9 mg, 0.016 mmol, 12.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.13 (1H, s), 7.63 (1H, dd, J=8.51,1.65 Hz), 7.96 (1H, s), 8.11 (1H, d, J=8.51 Hz), 8.67 (1H, s), 9.16 (1H,s), 10.82 (1H, s); ESIMS found for C₂₃H₁₃[²H₇]N₄O m/z 376.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-fluorophenyl)acetamide-2,2-d₂ 92.

Brown solid (18.1 mg, 0.048 mmol, 38.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.38 (3H, s), 3.65 (3H, s), 7.11 (1H, s), 7.16 (2H, t,J=8.92 Hz), 7.41 (2H, dd, J=8.10, 5.63 Hz), 7.61 (1H, dd, J=8.51, 1.65Hz), 7.89 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.47 (1H, s), 9.13 (1H, s),10.83 (1H, s); ESIMS found for C₂₂H₁₇[²H₂]FN₄O m/z 377.2 (M+1).

(E)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-(phenyl-2,3,4,5,6-d₅)acrylamide93.

Off-white solid (15.9 mg, 0.044 mmol, 35.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.13 (1H, d, J=15.92 Hz), 7.32 (1H, s),7.67 (1H, d, J=15.64 Hz), 7.70 (1H, dd, J=8.37, 1.78 Hz), 7.81 (1H, s),8.06 (1H, s), 8.12 (1H, d, J=8.78 Hz), 8.69 (1H, s), 9.17 (1H, s), 10.83(1H, s); ESIMS found for C₂₂H₁₃[²H₅]N₄O m/z 360.2 (M+1).

(E)-N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-(phenyl-2,3,4,5,6-d₅)acrylamide-2,3-d₂94.

Off-white solid (16.2 mg, 0.045 mmol, 35.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.32 (1H, s), 7.70 (1H, dd, J=8.37, 1.51Hz), 7.80 (1H, s), 8.05 (1H, s), 8.12 (1H, d, J=8.51 Hz), 8.69 (1H, s),9.17 (1H, s), 10.83 (1H, s); ESIMS found for C₂₂H₁₁[²H₇]N₄O m/z 362.2(M+1).

2-(4-Fluorophenyl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)acetamide-2,2-d₂ 95.

Off-white solid (14.1 mg, 0.039 mmol, 30.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.81 (3H, s), 7.12-7.20 (2H, m), 7.29 (1H, d, J=0.82 Hz),7.41 (2H, dd, J=7.96, 5.76 Hz), 7.68 (1H, dd, J=8.51, 1.65 Hz), 7.78(1H, s), 7.99 (1H, s), 8.09 (1H, d, J=8.51 Hz), 8.49 (1H, s), 9.14 (1H,s), 10.84 (1H, s); ESIMS found for C₂₁H₁₅[²H₂]FN₄O m/z 363.2 (M+1).

cis-4-(Dimethylamino)-N-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 96.

White solid (2.0 mg, 0.005 mmol, 1.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.48-1.57 (4H, m), 1.81-1.93 (4H, m), 2.19 (6H, br s), 2.21-2.25(1H, m), 2.67-2.73 (1H, m), 3.90 (3H, s), 7.56-7.61 (1H, m), 7.93 (1H,s), 8.12 (1H, s), 8.39 (1H, s), 8.48 (1H, s), 9.14 (1H, s), 10.51 (1H,s); ESIMS found for C₂₂H₂₆FN₅O m/z 396.2 (M+1).

cis-N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide97.

Off-white solid (20.0 mg, 0.046 mmol, 16.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.42-1.57 (4H, m), 1.82-1.97 (4H, m), 2.13-2.20 (1H, m),2.41 (4H, br s), 2.70 (1H, tt, J=7.82, 3.98 Hz), 3.59 (4H, t, J=4.39Hz), 3.90 (3H, s), 7.58 (1H, dd, J=12.08, 1.10 Hz), 7.91 (1H, s), 8.11(1H, s), 8.39 (1H, s), 8.48 (1H, s), 9.14 (1H, s), 10.51 (1H, s); ESIMSfound for C₂₄H₂₈FN₅O₂ m/z 438.2 (M+1).

trans-N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide99.

Off-white solid (26.0 mg, 0.064 mmol, 30.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.12-1.23 (2H, m), 1.44-1.55 (2H, m), 1.65 (4H, br t,J=3.16 Hz), 1.88 (2H, br d, J=12.35 Hz), 1.94-2.05 (3H, m), 2.46-2.49(4H, m), 2.51-2.56 (1H, m), 4.14 (3H, s), 8.00 (1H, dd, J=8.51, 1.37Hz), 8.10 (1H, d, J=8.78 Hz), 8.27 (1H, s), 8.50 (1H, s), 8.72 (1H, s),9.10 (1H, s), 10.48 (1H, s); ESIMS found for C₂₃H₂₇N₆O m/z 405.2 (M+1).

trans-N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-4-morpholinocyclohexane-1-carboxamide100.

Off-white solid (60.0 mg, 0.143 mmol, 66.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.15-1.28 (2H, m), 1.42-1.56 (2H, m), 1.91 (4H, br t,J=12.62 Hz), 2.17-2.26 (1H, m), 2.45-2.49 (4H, m), 2.51-2.53 (1H, m),3.53-3.59 (4H, m), 4.14 (3H, s), 8.01 (1H, dd, J=8.51, 1.65 Hz), 8.10(1H, d, J=8.78 Hz), 8.27 (1H, s), 8.49 (1H, s), 8.72 (1H, s), 9.11 (1H,s), 10.50 (1H, s); ESIMS found for C₂₃H₂₈N₆O₂ m/z 421.2 (M+1).

trans-N-(8-Fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide101.

Off-white solid (83.0 mg, 0.173 mmol, 61.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.36-1.47 (2H, m), 1.51-1.62 (2H, m), 1.72 (2H, br d,J=11.25 Hz), 1.89 (2H, br d, J=10.15 Hz), 2.18 (3H, s), 2.23 (2H, br s),2.30 (2H, br s), 2.53 (3H, s), 2.55-2.60 (1H, m), 2.61-2.68 (1H, m),3.44 (2H, br s), 3.50 (2H, br s), 7.62-7.68 (1H, m), 7.84 (1H, s), 7.96(1H, s), 8.57 (1H, s), 9.22 (1H, s), 10.67 (1H, s); ESIMS found forC₂₆H₃₀FN₅O₃ m/z 480.3 (M+1).

trans-N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(4-methylpiperazine-1-carbonyl)cyclohexane-1-carboxamide102.

Off-white solid (55.0 mg, 0.115 mmol, 40.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.35-1.47 (2H, m), 1.57 (2H, qd, J=12.76, 2.88 Hz), 1.72(2H, br d, J=10.98 Hz), 1.89 (2H, br d, J=10.43 Hz), 2.18 (3H, s), 2.23(2H, br s), 2.30 (2H, br s), 2.52-2.60 (1H, m), 2.64 (1H, tt, J=11.53,3.16 Hz), 3.44 (2H, br s), 3.50 (2H, br s), 3.90 (3H, s), 7.54-7.62 (1H,m), 7.92 (1H, s), 8.11 (1H, s), 8.39 (1H, s), 8.49 (1H, s), 9.15 (1H,s), 10.58 (1H, s); ESIMS found for C₂₆H₃₁FN₆O₂ m/z 479.25 (M+1).

trans-4-((2,2-Difluoroethyl)amino)-N-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide103.

White solid (7.0 mg, 0.016 mmol, 8.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 0.96-1.07 (2H, m), 1.47 (2H, qd, J=12.90, 3.29 Hz), 1.87 (3H, brd, J=10.98 Hz), 1.93-2.00 (2H, m), 2.35-2.44 (1H, m), 2.51-2.56 (1H, m),2.91 (2H, td, J=15.92, 4.39 Hz), 3.89 (3H, s), 5.94 (1H, tt, J=56.90,4.40 Hz), 7.58 (1H, dd, J=12.08, 1.37 Hz), 7.91 (1H, s), 8.11 (1H, s),8.39 (1H, s), 8.48 (1H, s), 9.14 (1H, s), 10.57 (1H, s); ESIMS found forC₂₂H₂₄F₃N₅O m/z 432.2 (M+1).

trans-4-((2,2-Difluoroethyl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide104.

White solid (10.0 mg, 0.024 mmol, 8.5% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.97-1.09 (2H, m), 1.47 (2H, qd, J=12.90, 3.02 Hz), 1.86 (3H, brd, J=11.53 Hz), 1.93-1.99 (2H, m), 2.34-2.43 (1H, m), 2.51-2.54 (1H, m),2.53 (3H, s), 2.91 (2H, td, J=15.92, 4.12 Hz), 5.94 (1H, tt, J=56.80,4.40 Hz), 7.78 (1H, s), 7.79-7.84 (1H, m), 8.06-8.13 (2H, m), 8.50 (1H,s), 9.10 (1H, s), 10.51 (1H, s); ESIMS found for C₂₂H₂₄F₂N₄O₂ m/z 415.2(M+1).

trans-N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((2-methoxyethyl)amino)cyclohexane-1-carboxamide105.

Beige solid (4.0 mg, 0.009 mmol, 4.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.24-1.36 (2H, m), 1.44-1.55 (2H, m), 1.91-1.99 (2H, m), 2.02-2.15(2H, m), 2.52 (1H, br d, J=1.92 Hz), 2.53-2.59 (1H, m), 3.04 (2H, br s),3.29 (3H, br s), 3.53 (2H, br s), 3.90 (3H, s), 7.59 (1H, dd, J=12.08,1.10 Hz), 7.89-7.93 (1H, m), 8.11-8.14 (1H, m), 8.39 (1H, s), 8.46-8.50(1H, m), 9.15 (1H, s), 10.61 (1H, s); ESIMS found for C₂₃H₂₈FN₅O₂ m/z426.2 (M+1).

trans-4-((2-Methoxyethyl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide106.

White solid (8.0 mg, 0.020 mmol, 6.9% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.97-1.07 (2H, m), 1.43-1.54 (2H, m), 1.86 (2H, br d, J=11.53 Hz),1.91-1.98 (2H, m), 2.34-2.42 (1H, m), 2.51-2.53 (1H, m), 2.53 (3H, s),2.70 (2H, t, J=5.63 Hz), 3.24 (3H, s), 3.37 (3H, t, J=5.76 Hz), 7.78(1H, s), 7.81 (1H, dd, J=8.64, 1.51 Hz), 8.07-8.12 (2H, m), 8.50 (1H,s), 9.10 (1H, s), 10.50 (1H, s); ESIMS found for C₂₃H₂₈N₄O₃ m/z 409.2(M+1).

3-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide108.

Pale yellow solid (23.0 mg, 0.058 mmol, 7.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.75-1.87 (4H, m), 2.10-2.21 (2H, m), 2.15 (3H, s), 2.62(2H, dd, J=10.84, 2.33 Hz), 2.82 (3H, s), 4.50 (2H, br s), 8.03 (1H, dd,J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.78 Hz), 8.38 (1H, s), 8.40 (1H, s),9.16 (1H, s), 9.35 (1H, s); ESIMS found for C₂₀H₂₂N₆OS m/z 395.2 (M+1).

(R)-3,4-Dimethyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperazine-1-carboxamide 109.

Pale yellow solid (27.0 mg, 0.071 mmol, 8.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.02 (3H, d, J=6.31 Hz), 1.98 (1H, dqd, J=9.67, 6.29,6.29, 6.29, 3.29 Hz), 2.07 (1H, td, J=11.53, 3.02 Hz), 2.19 (3H, s),2.62 (1H, dd, J=12.90, 10.15 Hz), 2.74 (1H, dt, J=11.53, 2.74 Hz), 2.82(3H, s), 2.95-3.02 (1H, m), 4.00-4.10 (2H, m), 8.02 (1H, dd, J=8.51,1.65 Hz), 8.15 (1H, d, J=8.78 Hz), 8.31 (1H, s), 8.38 (1H, d, J=0.82Hz), 9.16 (1H, s), 9.32 (1H, s); ESIMS found for C₁₉H₂₂N₆OS m/z 383.2(M+1).

8-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxamide110.

Beige solid (20.0 mg, 0.051 mmol, 6.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.52-1.62 (2H, m), 1.87-1.95 (2H, m), 2.19 (3H, s), 2.82 (3H, s),3.03 (2H, br d, J=11.53 Hz), 3.08-3.14 (2H, m), 3.80 (2H, dd, J=12.35,2.47 Hz), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.78 Hz), 8.31(1H, s), 8.38 (1H, d, J=0.82 Hz), 9.07 (1H, s), 9.15 (1H, s); ESIMSfound for C₂₀H₂₂N₆OS m/z 395.2 (M+1).

4-((1,3-Difluoropropan-2-yl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 121.

Off-white solid (20.0 mg, 0.045 mmol, 16.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.16-1.27 (2H, m), 1.83 (2H, br dd, J=12.90, 3.02 Hz),2.76-2.85 (1H, m), 2.82 (3H, s), 2.90-3.00 (2H, m), 3.11-3.23 (1H, m),4.09 (2H, br d, J=13.45 Hz), 4.32-4.51 (4H, m), 8.02 (1H, dd, J=8.51,1.65 Hz), 8.15 (1H, d, J=8.51 Hz), 8.30 (1H, s), 8.37 (1H, s), 9.15 (1H,s), 9.29 (1H, s); ESIMS found for C₂₁H₂₄F₂N₆OS m/z 447.2 (M+1).

trans-4-((1,3-Difluoropropan-2-yl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 124.

Off-white solid (20.0 mg, 0.047 mmol, 14.2% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.98-1.09 (2H, m), 1.42-1.54 (2H, m), 1.65 (1H, br s),1.82-1.89 (2H, m), 1.91-1.98 (2H, m), 2.51-2.60 (1H, m), 2.53 (3H, s),4.30-4.51 (4H, m), 7.78 (1H, s), 7.81 (1H, dd, J=8.64, 1.51 Hz), 8.09(2H, dd, J=4.67, 3.84 Hz), 8.50 (1H, s), 9.10 (1H, s), 10.51 (1H, s);ESIMS found for C₂₃H₂₆F₂N₄O₂ m/z 429.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxamide 125.

Beige solid (48.0 mg, 0.123 mmol, 29.7% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.82 (3H, s), 3.95-4.01 (2H, m), 4.06-4.12 (2H, m), 4.75(2H, s), 6.89 (1H, d, J=1.37 Hz), 7.12 (1H, d, J=1.37 Hz), 8.05 (1H, dd,J=8.51, 1.65 Hz), 8.17 (1H, d, J=8.51 Hz), 8.34 (1H, s), 8.41 (1H, d,J=0.82 Hz), 9.19 (1H, s), 9.74 (1H, s); ESIMS found for C₁₉H₁₇N₇OS m/z392.1 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxamide126.

Beige solid (53.0 mg, 0.142 mmol, 31.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.53 (3H, s), 3.94-4.02 (2H, m), 4.04-4.11 (2H, m), 4.74(2H, s), 6.89 (1H, d, J=1.37 Hz), 7.12 (1H, d, J=1.10 Hz), 7.77 (1H, dd,J=8.51, 1.65 Hz), 7.77 (1H, s), 8.03-8.12 (2H, m), 8.23 (1H, s), 9.09(1H, s), 9.65 (1H, s); ESIMS found for C₂₀H₁₈N₆O₂ m/z 375.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-morpholinopiperidine-1-carboxamide128.

Beige solid (55.0 mg, 0.125 mmol, 30.4% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.28-1.40 (2H, m), 1.80 (2H, br d, J=10.70 Hz), 2.32-2.40(1H, m), 2.44-2.49 (4H, m), 2.79-2.88 (2H, m), 2.82 (3H, s), 3.53-3.60(4H, m), 4.23 (2H, br d, J=13.45 Hz), 8.02 (1H, dd, J=8.51, 1.65 Hz),8.15 (1H, d, J=8.51 Hz), 8.30 (1H, s), 8.37 (1H, d, J=0.82 Hz), 9.15(1H, s), 9.32 (1H, s); ESIMS found for C₂₂H₂₆N₆O₂S m/z 439.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide129.

Off-white solid (45.0 mg, 0.100 mmol, 12.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.34 (2H, qd, J=11.94, 3.98 Hz), 1.77 (2H, br d, J=10.98Hz), 2.13 (3H, s), 2.30 (4H, br s), 2.36-2.43 (1H, m), 2.43-2.54 (4H,m), 2.77-2.87 (2H, m), 2.82 (3H, s), 4.23 (2H, br d, J=13.17 Hz), 8.02(1H, dd, J=8.78, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz), 8.30 (1H, s), 8.37(1H, d, J=0.82 Hz), 9.15 (1H, s), 9.30 (1H, s); ESIMS found forC₂₃H₂₉N₇OS m/z 452.2 (M+1).

(3R,4R)-3-Fluoro-4-(isopropylamino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 130.

Beige solid (20.0 mg, 0.04 mmol, 24.4% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 0.98 (3H, d, J=6.31 Hz), 1.01 (3H, d, J=6.31 Hz), 1.27-1.36 (1H,m), 1.86-1.95 (1H, m), 2.82 (3H, s), 2.85-2.97 (2H, m), 3.22-3.29 (1H,m), 3.35-3.43 (1H, m), 3.75-3.84 (1H, m), 4.04 (1H, ddd, J=17.70, 13.86,3.57 Hz), 4.33 (1H, dtd, J=47.8, 7.14, 3.84 Hz), 8.03 (1H, dd, J=8.51,1.65 Hz), 8.16 (1H, d, J=8.51 Hz), 8.29 (1H, s), 8.39 (1H, s), 9.17 (1H,s), 9.43 (1H, s); ESIMS found for C₂₁H₂₅FN₆OS m/z 429.2 (M+1).

(3R,4R)-4-Amino-3-fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide131.

Beige solid (200.0 mg, 0.518 mmol, 71.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.28-1.39 (1H, m), 1.80-1.88 (1H, m), 2.82 (3H, s),2.86-2.94 (1H, m), 3.14 (1H, ddd, J=13.17, 10.02, 2.61 Hz), 3.18-3.24(1H, m), 3.86-3.94 (1H, m), 4.12-4.17 (1H, m), 4.18-4.29 (1H, m), 8.03(1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d, J=8.78 Hz), 8.30 (1H, s), 8.39(1H, s), 9.17 (1H, s), 9.47 (1H, s); ESIMS found for C₁₈H₁₉FN₆OS m/z387.2 (M+1).

1-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide 134.

Beige solid (10.0 mg, 0.027 mmol, 16.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.74 (2H, m), 1.76-1.84 (2H, m), 1.86-1.96 (2H, m),2.18 (3H, s), 2.52-2.58 (1H, m), 2.79-2.87 (5H, m), 8.09 (1H, dd,J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.78 Hz), 8.44 (1H, s), 9.21 (1H, s),10.64 (1H, s); ESIMS found for C₁₉H₂₀[²H]N₅OS m/z 369.15 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl-4-d)-2-morpholinoacetamide135.

Beige solid (3.0 mg, 0.008 mmol, 3.6% yield). 2.57-2.61 (4H, m), 2.83(3H, s), 3.27 (2H, s), 3.63-3.69 (4H, m), 8.12 (1H, dd, J=8.51, 1.65Hz), 8.21 (1H, d, J=8.51 Hz), 8.51 (1H, d, J=1.37 Hz), 9.23 (1H, s),10.17 (1H, s); ESIMS found for C₁₈H₁₈[²H]N₅O₂S m/z 371.1 (M+1).

1-Methyl-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl-4-d)piperidine-4-carboxamide136.

Beige solid (20.0 mg, 0.057 mmol, 32.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64-1.75 (2H, m), 1.76-1.84 (2H, m), 1.89-1.99 (2H, m),2.20 (3H, s), 2.51-2.57 (1H, m), 2.53 (3H, s), 2.85 (2H, br d, J=11.25Hz), 7.78 (1H, s), 7.81 (1H, dd, J=8.78, 1.65 Hz), 8.06-8.12 (2H, m),9.10 (1H, s), 10.56 (1H, s); ESIMS found for C₂₀H₂₁[²H]N₄O₂ m/z 352.15(M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl-4-d)-2-morpholinoacetamide137.

Light orange solid (18.0 mg, 0.051 mmol, 32.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.53 (3H, s), 2.55-2.60 (4H, m), 3.25 (2H, s), 3.63-3.69(4H, m), 7.80 (1H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.12 (1H, d,J=8.51 Hz), 8.16 (1H, s), 9.12 (1H, s), 10.08 (1H, s); ESIMS found forC₁₉H₁₉[²H]N₄O₃ m/z 354.15 (M+1).

(3S,4S)-3-Fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-((propan-2-yl-1,1,1,3,3,3-d₆)amino)piperidine-1-carboxamide139.

Off-white solid (45.0 mg, 0.104 mmol, 80.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.27-1.36 (1H, m), 1.60 (1H, br s), 1.86-1.95 (1H, m),2.82 (3H, s), 2.83-2.93 (2H, m), 3.22-3.30 (1H, m), 3.36-3.42 (1H, m),3.74-3.84 (1H, m), 3.98-4.09 (1H, m), 4.25-4.42 (1H, m), 8.03 (1H, dd,J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz), 8.29 (1H, s), 8.38 (1H, s),9.16 (1H, s), 9.42 (1H, s); ESIMS found for C₂₁H₁₉[²H₆]FN₆OS m/z 435.2(M+1).

trans-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-4-((propan-2-yl-1,1,1,3,3,3-d₆)amino)cyclohexane-1-carboxamide141.

Beige solid (48.0 mg, 0.120 mmol, 84.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.96-1.05 (2H, m), 1.13 (1H, br s), 1.49 (2H, qd,J=12.90, 3.02 Hz), 1.85 (2H, br d, J=11.53 Hz), 1.92 (2H, br dd,J=12.76, 2.88 Hz), 2.41-2.47 (1H, m), 2.47-2.51 (1H, m), 2.53 (3H, s),2.85-2.92 (1H, m), 7.78 (1H, s), 7.80 (1H, dd, J=8.78, 1.37 Hz),8.06-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.49 (1H, s); ESIMSfound for C₂₃H₂₂[²H₆]N₄O₂ m/z 399.25 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)morpholine-d₈-4-carboxamide143.

Off-white solid (35.0 mg, 0.10 mmol, 23.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.39 (3H, s), 3.65 (3H, s), 7.09 (1H, s), 7.54 (1H, dd,J=8.51, 1.65 Hz), 7.84 (1H, s), 8.04 (1H, d, J=8.51 Hz), 8.22 (1H, s),9.07 (1H, s), 9.24 (1H, s); ESIMS found for C₁₉H₁₃[²H₈]N₅O₂ m/z 360.25(M+1).

trans-4-(Bis(methyl-d₃)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 144.

White solid (4.0 mg, 0.010 mmol, 6.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.13-1.24 (2H, m), 1.41-1.54 (2H, m), 1.82-1.95 (4H, m), 2.09-2.20(1H, m), 2.43-2.49 (1H, m), 2.53 (3H, s), 7.78 (1H, s), 7.79-7.82 (1H,m), 8.07-8.11 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.50 (1H, s); ESIMSfound for C₂₂H₂₀[²H₆]N₄O₂ m/z 385.3 (M+1).

trans-4-(Bis(methyl-d₃)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide145.

White solid (17.0 mg, 0.044 mmol, 10.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.12-1.22 (2H, m), 1.42-1.54 (2H, m), 1.83-1.95 (4H, m),2.14 (1H, tt, J=11.49, 3.33 Hz), 2.43-2.49 (1H, m), 3.90 (3H, s), 7.74(1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.07(1H, s), 8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMSfound for C₂₂H₂₁[²H₆]N₅O m/z 384.25 (M+1).

4-Isopropyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperazine-1-carboxamide 146.

Beige solid (4.0 mg, 0.010 mmol, 1.2% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.98 (6H, d, J=6.59 Hz), 2.43-2.47 (4H, m), 2.62-2.72 (1H, m),2.82 (3H, s), 3.47-3.54 (4H, m), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15(1H, d, J=8.51 Hz), 8.31 (1H, s), 8.37 (1H, s), 9.16 (1H, s), 9.29 (1H,s); ESIMS found for C₂₀H₂₄N₆OS m/z 397.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-((3,3,3-trifluoropropyl)amino)piperidine-1-carboxamide147.

Off-white solid (20.0 mg, 0.043 mmol, 24.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.14-1.25 (2H, m), 1.77-1.85 (3H, m), 2.35-2.42 (2H, m),2.59-2.67 (1H, m), 2.73-2.80 (2H, m), 2.82 (3H, s), 2.91-3.01 (2H, m),4.05-4.12 (2H, m), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.78Hz), 8.30 (1H, s), 8.37 (1H, d, J=0.82 Hz), 9.15 (1H, s), 9.29 (1H, s);ESIMS found for C₂₁H₂₃F₃N₆OS m/z 465.2 (M+1).

trans-N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-4-((3,3,3-trifluoropropyl)amino)cyclohexane-1-carboxamide 148.

Off-white solid (25.0 mg, 0.056 mmol, 19.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.97-1.09 (2H, m), 1.44-1.56 (2H, m), 1.83-1.90 (2H, m),1.94 (2H, br dd, J=12.21, 2.33 Hz), 2.31-2.43 (3H, m), 2.52-2.55 (1H,m), 2.53 (3H, s), 2.76 (2H, t, J=7.41 Hz), 7.78 (1H, s), 7.81 (1H, dd,J=8.64, 1.51 Hz), 8.05-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.50(1H, s); ESIMS found for C₂₃H₂₅F₃N₄O₂ m/z 447.2 (M+1).

trans-4-Amino-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide149.

Beige solid (370.0 mg, 1.056 mmol, 95.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.98-1.11 (2H, m), 1.43-1.54 (2H, m), 1.82 (4H, br d,J=11.53 Hz), 2.43-2.49 (1H, m), 2.52 (1H, br s), 2.53 (3H, s), 7.78 (1H,s), 7.79-7.83 (1H, m), 8.06-8.12 (2H, m), 8.49 (1H, s), 9.10 (1H, s),10.49 (1H, s); ESIMS found for C₂₀H₂₂N₄O₂ m/z 351.2 (M+1).

4-Amino-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide150.

Beige solid (400.0 mg, 1.086 mmol, 53.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.12-1.23 (2H, m), 1.72 (2H, br dd, J=12.90, 3.02 Hz),2.72-2.80 (1H, m), 2.82 (3H, s), 2.88-2.96 (2H, m), 4.05-4.13 (2H, m),8.02 (1H, dd, J=8.51, 1.65 Hz), 8.14 (1H, d, J=8.51 Hz), 8.30 (1H, s),8.37 (1H, s), 9.15 (1H, s), 9.26 (1H, s); ESIMS found for C₁₈H₂₀N₆OS m/z369.2 (M+1).

(1R,5S)-3-exo-Amino-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxamide151.

Beige solid (100.0 mg, 0.254 mmol, 62.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.35-1.43 (2H, m), 1.64-1.70 (2H, m), 1.70-1.76 (2H, m),1.85-1.92 (2H, m), 2.82 (3H, s), 3.06 (1H, tt, J=10.94, 5.39 Hz), 4.49(2H, br s), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz),8.37 (1H, s), 8.42 (1H, s), 9.16 (1H, s), 9.18 (1H, s); ESIMS found forC₂₀H₂₂N₆OS m/z 395.2 (M+1).

(1R,5S)-N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-3-exo-((3,3,3-trifluoropropyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxamide153.

Beige solid (8.0 mg, 0.016 mmol, 19.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.37 (2H, br t, J=10.98 Hz), 1.63 (1H, br s), 1.68-1.75 (2H, m),1.79-1.86 (2H, m), 1.86-1.93 (2H, m), 2.26-2.39 (2H, m), 2.71 (2H, t,J=7.55 Hz), 2.82 (3H, s), 2.94 (1H, tt, J=10.74, 5.32 Hz), 4.52 (2H, brs), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz), 8.37 (1H,s), 8.41 (1H, s), 9.16 (1H, s), 9.21 (1H, s); ESIMS found forC₂₃H₂₅F₃N₆OS m/z 491.2 (M+1).

trans-4-(2-(fluoromethyl)aziridin -1-yl)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 154.

Off-white solid (10.0 mg, 0.025 mmol, 7.4% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.17-1.33 (4H, m), 1.35-1.45 (3H, m), 1.87 (4H, br d,J=9.88 Hz), 2.51-2.59 (1H, m), 2.53 (3H, s), 3.97-4.14 (2H, m),4.36-4.50 (1H, m), 7.76-7.79 (1H, m), 7.80 (1H, dd, J=8.64, 1.51 Hz),8.06-8.13 (2H, m), 8.49 (1H, s), 9.10 (1H, s), 10.51 (1H, s); ESIMSfound for C₂₃H₂₅FN₄O₂ m/z 409.2 (M+1).

trans-4-((2-fluoroethyl)amino)-N-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 155.

White solid (25.0 mg, 0.063 mmol, 34.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.95-1.08 (2H, m), 1.49 (2H, qd, J=12.85, 3.16 Hz), 1.87(2H, br d, J=11.25 Hz), 1.92-2.00 (2H, m), 2.37-2.43 (1H, m), 2.51-2.55(1H, m), 2.53 (2H, s), 2.83 (2H, dt, J=27.00, 4.90 Hz), 4.44 (2H, dt,J=48.10, 5.00 Hz), 7.78 (1H, s), 7.80 (1H, dd, J=8.64, 1.51 Hz),8.07-8.12 (2H, m), 8.50 (1H, s), 9.10 (1H, s), 10.50 (1H, s); ESIMSfound for C₂₂H₂₅FN₄O₂ m/z 397.2 (M+1).

4-((2-Fluoroethyl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide156.

Beige solid (10.0 mg, 0.024 mmol, 15.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.38-1.49 (2H, m), 1.82-1.90 (2H, m), 2.17-2.26 (2H, m),2.58-2.68 (2H, m), 2.74-2.81 (2H, m), 2.82 (3H, s), 3.53-3.61 (1H, m),4.53 (2H, dt, J=47.80, 5.00 Hz), 7.99 (1H, dd, J=8.51, 1.65 Hz), 8.12(1H, d, J=8.78 Hz), 8.19 (1H, s), 8.33 (1H, d, J=0.82 Hz), 9.06 (1H, s),9.11 (1H, s); ESIMS found for C₂₀H₂₃FN₆OS m/z 415.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-fluorobenzamide-3,4,5,6-d₄157.

Brown solid (6.4.0 mg, 0.018 mmol, 20.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.69 (3H, s), 7.15 (1H, s), 7.66 (1H, dd,J=8.51, 1.65 Hz), 8.01 (1H, s), 8.13 (1H, d, J=8.78 Hz), 8.66 (1H, s),9.18 (1H, s), 10.87 (1H, s); ESIMS found for C₂₁H₁₃[²H₄]FN₄O m/z 365.2(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-fluorobenzamide-2,3,5,6-d₄158.

Brown solid (7.8 mg, 0.021 mmol, 17.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.40 (3H, s), 3.69 (3H, s), 7.15 (1H, s), 7.66 (1H, dd, J=8.51,1.65 Hz), 8.00 (1H, s), 8.14 (1H, d, J=8.51 Hz), 8.67 (1H, s), 9.21 (1H,s), 10.95 (1H, s); ESIMS found for C₂₁H₁₃[²H₄]FN₄O m/z 365.15 (M+1).

2-Chloro-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-3,4,5,6-d₄159.

Brown solid (10.1 mg, 0.027 mmol, 31.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.69 (3H, s), 7.15 (1H, s), 7.66 (1H, dd,J=8.51, 1.65 Hz), 8.02 (1H, s), 8.12 (1H, d, J=8.51 Hz), 8.66 (1H, s),9.16 (1H, s), 11.12 (1H, s); ESIMS found for C₂₁H₁₃[²H₄]ClN₄O m/z 381.(M+1).

4-Chloro-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide-2,3,5,6-d₄160.

Brown solid (15.0 mg, 0.039 mmol, 31.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.14 (1H, s), 7.66 (1H, dd,J=8.51, 1.65 Hz), 8.00 (1H, s), 8.14 (1H, d, J=8.78 Hz), 8.67 (1H, s),9.21 (1H, s), 11.01 (1H, s); ESIMS found for C₂₁H₁₃[²H₄]ClN₄O m/z 381.15(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(methyl-d₃)benzamide 161.

Brown solid (10.6 mg, 0.030 mmol, 35.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.41 (3H, s), 3.69 (3H, s), 7.15 (1H, s), 7.31-7.37 (2H,m), 7.65 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, br s), 7.99-8.04 (2H, m),8.11-8.16 (1H, m), 8.67 (1H, s), 9.20 (1H, s), 10.77 (1H, s); ESIMSfound for C₂₂H₁₇[²H₃]N₄O m/z 360.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-methylbenzamide-2,3,5,6-d₄162.

Brown solid (9.3 mg, 0.026 mmol, 30.7% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.40 (3H, s), 2.40 (3H, s), 3.68 (3H, s), 7.14 (1H, s), 7.65 (1H,dd, J=8.23, 1.65 Hz), 7.99 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.67 (1H,s), 9.20 (1H, s), 10.77 (1H, s); ESIMS found for C₂₂H₁₆[²H₄]N₄O m/z 361.(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(methyl-d₃)benzamide-2,3,5,6-d₄ 163.

Brown solid (8.4 mg, 0.023 mmol, 18.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.14 (1H, s), 7.65 (1H, dd, J=8.51,1.65 Hz), 7.99 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.67 (1H, s), 9.20 (1H,s), 10.78 (1H, s); ESIMS found for C₂₂H₁₃[²H₇]N₄O m/z 364.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(methoxy-d₃)benzamide 164.

Brown solid (10.5 mg, 0.028 mmol, 33.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.42 (3H, s), 3.69 (3H, s), 7.06 (2H, d, J=8.78 Hz), 7.19(1H, s), 7.64 (1H, dd, J=8.37, 1.51 Hz), 7.99 (1H, s), 8.07-8.12 (2H,m), 8.13 (1H, d, J=8.51 Hz), 8.67 (1H, s), 9.20 (1H, s), 10.71 (1H, s);ESIMS found for C₂₂H₁₇[²H₃]N₄O₂ m/z 376.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(methoxy-d₃)benzamide-2,3,5,6-d4 165.

Brown solid (11.1 mg, 0.029 mmol, 23.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.68 (3H, s), 7.14 (1H, s), 7.64 (1H, dd,J=8.51, 1.65 Hz), 7.98 (1H, s), 8.13 (1H, d, J=8.51 Hz), 8.66 (1H, s),9.19 (1H, s), 10.71 (1H, s); ESIMS found for C₂₂H₁₃[²H₇]N₄O₂ m/z 380.2(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-methoxybenzamide-2,3,5,6-d₄166.

Brown solid (12.5 mg, 0.033 mmol, 39.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.44 (3H, s), 3.70 (3H, s), 3.85 (3H, s), 7.25 (1H, s),7.65 (1H, dd, J=8.23, 1.65 Hz), 8.01 (1H, s), 8.12-8.18 (1H, m), 8.68(1H, s), 9.21 (1H, s), 10.73 (1H, s); ESIMS found for C₂₂H₁₆[²H₄]N₄O₂m/z 377.2 (M+1).

1-(tert-Butyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide167.

Off-white solid (48.0 mg, 0.123 mmol, 24.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.02 (9H, s), 1.62 (2H, qd, J=12.17, 3.57 Hz), 1.79 (2H,br d, J=10.98 Hz), 1.98-2.09 (2H, m), 2.45-2.54 (1H, m), 3.03 (2H, br d,J=11.53 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d,J=8.51 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.34 (1H, s), 8.45 (1H, s), 9.02(1H, s), 10.43 (1H, s); ESIMS found for C₂₃H₂₉N₅O m/z 392.2 (M+1).

4-((2,2-Difluoroethyl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)piperidine-1-carboxamide 168.

White solid (1.0 mg, 0.0 mmol, % yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm1.38-1.49 (2H, m), 1.81-1.89 (2H, m), 2.30-2.37 (2H, m), 2.73 (2H, td,J=15.64, 4.39 Hz), 2.81 (2H, br s), 2.82 (3H, s), 3.53-3.62 (1H, m),6.13 (1H, tt, J=55.80, 4.40 Hz), 7.06 (1H, br d, J=6.59 Hz), 7.99 (1H,dd, J=8.51, 1.65 Hz), 8.13 (1H, d, J=8.51 Hz), 8.19 (1H, s), 8.33 (1H,s), 9.06 (1H, s), 9.11 (1H, s); ESIMS found for C₂₀H₂₂F₂N₆OS m/z 433.(M+1).

1-Butyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)piperidine-4-carboxamide169.

White solid (1.0 mg, 0.0 mmol, % yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm0.89 (3H, t, J=7.41 Hz), 1.29 (2H, sxt, J=7.35 Hz), 1.37-1.45 (2H, m),1.61-1.71 (2H, m), 1.73-1.80 (2H, m), 1.86 (2H, td, J=11.66, 2.20 Hz),2.22-2.28 (2H, m), 2.51-2.57 (1H, m), 2.90 (2H, br d, J=11.25 Hz), 3.90(3H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.03(1H, s), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.44 (1H, s), 9.02 (1H,s), 10.45 (1H, s); ESIMS found for C₂₃H₂₉N₅O m/z 392. (M+1).

1,1-Diisobutyl-4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)piperidin-1-ium 170.

Yellow-white solid (10.0 mg, 0.022 mmol, 17.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.07 (6H, d, J=6.6 Hz), 1.08 (6H, d, J=6.6 Hz), 2.12 (4H,br d, J=3.84 Hz), 2.18 (1H, br dd, J=13.31, 6.72 Hz), 2.21-2.28 (1H, m),2.84-2.93 (1H, m), 3.32-3.41 (6H, m), 3.63 (2H, br d, J=12.90 Hz), 3.91(3H, s), 7.77 (1H, dd, J=8.51, 1.65 Hz), 8.01-8.06 (2H, m), 8.09 (1H,s), 8.36 (1H, s), 8.40-8.47 (3H, m), 9.06 (1H, s), 10.72 (1H, s); ESIMSfound for C₂₇H₃₈N₅O m/z 449.3 (M+1).

(1R,4R)-5-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide176.

White solid (55.0 mg, 0.145 mmol, 40.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.66 (1H, br d, J=9.33 Hz), 1.81 (1H, br d, J=9.33 Hz),2.31 (3H, s), 2.53 (1H, br d, J=9.61 Hz), 2.79 (1H, dd, J=9.47, 2.06Hz), 2.82 (3H, s), 3.41 (1H, br s), 3.59 (1H, br d, J=9.61 Hz), 4.59(1H, br s), 8.02 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.78 Hz),8.37 (1H, s), 8.38 (1H, s), 9.02 (1H, br s), 9.15 (1H, s); ESIMS foundfor C₁₉H₂₀N₆OS m/z 381. (M+1).

(3S,4S)-3-Fluoro-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-(methylamino)piperidine-1-carboxamide179.

Beige solid (8.0 mg, 0.020 mmol, 15.42% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.30-1.40 (1H, m), 1.91 (1H, ddt, J=13.65, 9.95, 3.43,3.43 Hz), 2.34 (3H, s), 2.62-2.72 (1H, m), 2.82 (3H, s), 3.21-3.29 (2H,m), 3.35-3.44 (2H, m), 3.75-3.84 (1H, m), 3.96-4.07 (1H, m), 4.32-4.49(1H, m), 8.03 (1H, dd, J=8.51, 1.65 Hz), 8.15 (1H, d, J=8.51 Hz), 8.29(1H, s), 8.39 (1H, s), 9.16 (1H, s), 9.43 (1H, s); ESIMS found forC₁₉H₂₁FN₆OS m/z 401.2 (M+1).

(1R,5S)-cis-3-((2,2-difluoroethyl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxamide 188.

Off-white solid (10.0 mg, 0.022 mmol, 17.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.56 (1H, s), 1.59 (1H, s), 1.95 (4H, s), 2.09 (2H, ddd,J=14.41, 6.72, 3.29 Hz), 2.71 (2H, td, J=15.64, 4.39 Hz), 2.82 (3H, s),3.21 (2H, br s), 3.84-3.91 (1H, m), 6.02 (1H, tt, J=56.40, 4.70 Hz),7.99 (1H, dd, J=8.51, 1.65 Hz), 8.03 (1H, s), 8.14 (1H, d, J=8.78 Hz),8.32 (1H, s), 9.13 (1H, s), 9.41 (1H, s); ESIMS found for C₂₂H₂₄F₂N₆OSm/z 459.2 (M+1).

(1R,5S)-3-endo-Amino-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxamide193.

Beige solid (203.0 mg, 0.515 mmol, 84.8% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.43-1.49 (2H, m), 1.85 (2H, br dd, J=6.59, 1.37 Hz),1.98-2.05 (2H, m), 2.25 (2H, br d, J=7.41 Hz), 2.82 (3H, s), 2.98 (1H,tt, J=10.92, 5.36 Hz), 4.44 (2H, br s), 8.02 (1H, dd, J=8.51, 1.65 Hz),8.14 (1H, d, J=8.78 Hz), 8.37 (1H, s), 8.39 (1H, s), 9.14 (1H, s), 9.15(1H, s); ESIMS found for C₂₀H₂₂N₆OS m/z 395.2 (M+1).

trans-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide194.

White solid (5.0 mg, 0.011 mmol, 4.1% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 1.33-1.44 (2H, m), 1.59-1.70 (2H, m), 2.08 (4H, dt,J=8.37, 4.32 Hz), 2.29 (3H, s), 2.37 (1H, tt, J=11.53, 3.02 Hz), 2.52(4H, br s), 2.48 (1H, tt, J=12.04, 3.19 Hz), 2.69 (4H, br s), 2.86 (3H,s), 8.07-8.11 (1H, m), 8.11-8.14 (1H, m), 8.35 (1H, s), 8.55 (1H, s),9.10 (1H, s); ESIMS found for C₂₄H₃₀N₆OS m/z 451.2 (M+1).

(1R,5S)-cis-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-3-((3,3,3-trifluoropropyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxamide195.

White solid (10.0 mg, 0.020 mmol, 15.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.57 (1H, s), 1.59 (1H, s), 1.90-1.98 (4H, m), 2.05 (2H,ddd, J=14.48, 6.93, 3.57 Hz), 2.37-2.46 (2H, m), 2.51-2.55 (2H, m), 2.82(3H, s), 3.21 (2H, br s), 3.88 (1H, q, J=7.04 Hz), 7.66 (1H, br s), 7.99(1H, dd, J=8.51, 1.65 Hz), 8.04 (1H, s), 8.14 (1H, d, J=8.78 Hz), 8.32(1H, s), 9.13 (1H, s), 9.40 (1H, s); ESIMS found for C₂₃H₂₅F₃N₆OS m/z491.2 (M+1).

trans-4-((2-Methoxyethyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 196.

Beige solid (3.0 mg, 0.007 mmol, 2.6% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.96-1.08 (2H, m), 1.42-1.54 (3H, m), 1.85 (2H, br d, J=11.53 Hz),1.90-1.97 (2H, m), 2.32-2.39 (1H, m), 2.69 (2H, t, J=5.76 Hz), 3.24 (3H,s), 3.37 (2H, t, J=5.63 Hz), 3.90 (3H, s), 7.74 (1H, dd, J=8.51, 1.65Hz), 7.99 (1H, d, J=8.51 Hz), 8.02 (1H, s), 8.08 (1H, d, J=0.82 Hz),8.35 (1H, s), 8.42 (1H, s), 9.02 (1H, s), 10.41 (1H, s); ESIMS found forC₂₃H₂₉N₅O₂ m/z 408.2 (M+1).

trans-4-((2-Fluoroethyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide197.

White solid (41.0 mg, 0.10 mmol, 36.2% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.97-1.07 (2H, m), 1.48 (2H, qd, J=12.90, 3.02 Hz), 1.82-1.91 (2H,m), 1.93-2.01 (2H, m), 2.39 (1H, tt, J=10.87, 3.53 Hz), 2.83 (2H, dt,J=26.70, 5.20 Hz), 3.90 (3H, s), 4.44 (2H, dt, J=47.80, 5.30 Hz), 7.74(1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.78 Hz), 8.02 (1H, d, J=0.82Hz), 8.08 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.43 (1H, s), 9.02 (1H, s),10.42 (1H, s); ESIMS found for C₂₂H₂₆FN₅O m/z 396.2 (M+1).

trans-4-((2-Methoxyethyl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 199.

White solid (12.0 mg, 0.03 mmol, 14.4% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.96-1.06 (2H, m), 1.42-1.55 (3H, m), 1.87 (2H, br d, J=11.25 Hz),1.91-1.98 (2H, m), 2.36 (1H, tt, J=10.84, 3.70 Hz), 2.51-2.57 (1H, m),2.69 (2H, t, J=5.76 Hz), 2.82 (3H, s), 3.24 (3H, s), 3.37 (2H, t, J=5.63Hz), 8.08 (1H, dd, J=8.51, 1.65 Hz), 8.18 (1H, d, J=8.51 Hz), 8.43 (1H,s), 8.61 (1H, s), 9.20 (1H, s), 10.58 (1H, s); ESIMS found forC₂₂H₂₇N₅O₂S m/z 426.2 (M+1).

trans-4-((2-Fluoroethyl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)cyclohexane-1-carboxamide 200.

White solid (10.0 mg, 0.02 mmol, 13.5% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.99-1.09 (2H, m), 1.44-1.55 (2H, m), 1.85-1.92 (2H, m), 1.94-2.01(2H, m), 2.39-2.46 (1H, m), 2.52-2.57 (1H, m), 2.82-2.91 (2H, m), 2.83(3H, s), 4.46 (2H, dt, J=47.80, 5.20 Hz), 8.09 (1H, dd, J=8.51, 1.65Hz), 8.19 (1H, d, J=8.78 Hz), 8.44 (1H, s), 8.61 (1H, s), 9.21 (1H, s),10.59 (1H, s); ESIMS found for C₂₁H₂₄FN₅OS m/z 414.2 (M+1).

1-Methyl-4-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine 1-oxide 224.

Beige solid (75.0 mg, 0.17 mmol, 72.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.99 (2H, br d, J=10.70 Hz), 3.11 (3H, s), 3.41 (3H, td, J=11.46,3.16 Hz), 3.62-3.73 (2H, m), 4.15 (3H, s), 4.25 (2H, br d, J=13.45 Hz),7.21 (1H, dd, J=5.21, 1.10 Hz), 7.56 (1H, s), 8.08 (1H, dd, J=8.51, 1.37Hz), 8.18 (1H, d, J=8.51 Hz), 8.29 (1H, d, J=5.21 Hz), 8.39 (1H, s),8.67 (1H, s), 8.76 (1H, s), 9.22 (1H, s), 11.17 (1H, s); ESIMS found forC₂₃H₂₄N₈O₂ m/z 445.2 (M+1).

1-Methyl-4-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)-1-oxidopyridin-2-yl)piperazine 1-oxide 225.

White solid (12.0 mg, 0.03 mmol, 11.2% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.88 (2H, br d, J=11.25 Hz), 3.03 (2H, br d, J=11.53 Hz), 3.22(3H, s), 4.13 (3H, s), 4.34 (2H, br t, J=10.98 Hz), 4.81-4.90 (2H, m),7.85 (1H, br d, J=8.23 Hz), 7.98 (1H, br d, J=7.96 Hz), 8.12 (1H, br d,J=4.39 Hz), 8.15 (1H, br s), 8.54 (1H, s), 8.56 (1H, br d, J=4.94 Hz),8.70 (1H, s), 9.04 (1H, s), 9.06 (1H, s), 11.44 (1H, br s); ESIMS foundfor C₂₃H₂₄N₈O₃ m/z 461.1 (M+1).

1-(Methyl-d3)-4-(4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine 1-oxide 226.

Beige solid (35.0 mg, 0.08 mmol, 33.8% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.99 (2H, br d, J=10.43 Hz), 3.40 (2H, td, J=11.53, 3.02 Hz),3.62-3.73 (2H, m), 4.15 (3H, s), 4.25 (2H, br d, J=13.45 Hz), 7.21 (1H,dd, J=5.21, 1.10 Hz), 7.56 (1H, s), 8.08 (1H, dd, J=8.51, 1.37 Hz), 8.18(1H, d, J=8.51 Hz), 8.30 (1H, d, J=5.21 Hz), 8.39 (1H, s), 8.67 (1H, s),8.76 (1H, s), 9.22 (1H, s), 11.16 (1H, s); ESIMS found forC₂₃H₂₁[²H₃]N₈O₂ m/z 448.2 (M+1).

3-(8-Fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea227.

Beige solid (95.0 mg, 0.23 mmol, 37.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.50-1.58 (2H, m), 1.75 (2H, qd, J=12.08, 3.84 Hz), 1.97 (2H, brt, J=10.84 Hz), 2.17 (3H, s), 2.78-2.87 (5H, m), 2.89 (3H, s), 4.04-4.14(1H, m), 7.78 (1H, d, J=10.98 Hz), 8.25 (1H, s), 8.40 (1H, s), 9.19 (1H,s), 9.26 (1H, s); ESIMS found for C₂₀H₂₃FN₆OS m/z 415.2 (M+1).

3-(8-Fluoro-6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea228.

Beige solid (92.0 mg, 0.23 mmol, 59.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.53 (2H, br d, J=9.61 Hz), 1.74 (2H, qd, J=12.12, 3.70 Hz), 1.98(2H, td, J=11.60, 1.78 Hz), 2.17 (3H, s), 2.83 (2H, br d, J=11.53 Hz),2.89 (3H, s), 4.09 (1H, tt, J=11.94, 4.12 Hz), 4.14 (3H, s), 7.70 (1H,d, J=11.53 Hz), 8.09 (1H, s), 8.28 (1H, s), 8.74 (1H, s), 9.05 (1H, s),9.18 (1H, s); ESIMS found for C₂₀H₂₄FN₇O m/z 398.2 (M+1).

3-(8-Fluoro-6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea229.

White solid (140.0 mg, 0.35 mmol, 42.8% yield). ¹H NMR (499 MHz, DMSO-d)6 ppm 1.49-1.57 (2H, m), 1.74 (2H, qd, J=12.08, 3.84 Hz), 1.97 (2H, td,J=11.73, 2.06 Hz), 2.17 (3H, s), 2.53 (3H, s), 2.82 (2H, br d, J=11.53Hz), 2.88 (3H, s), 4.09 (1H, tt, J=11.90, 4.01 Hz), 7.57 (1H, dd,J=11.53, 1.10 Hz), 7.81 (1H, s), 7.88 (1H, s), 8.28 (1H, s), 9.06 (1H,s), 9.16 (1H, s); ESIMS found for C₂₁H₂₄FN₅O₂ m/z 398.2 (M+1).

3-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1-methyl-1-(1-methylpiperidin-4-yl)urea230.

Beige solid (110.0 mg, 0.28 mmol, 67.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.49-1.57 (2H, m), 1.74 (2H, qd, J=12.12, 3.70 Hz), 1.97(2H, td, J=11.66, 1.92 Hz), 2.17 (3H, s), 2.82 (2H, br d, J=11.25 Hz),2.88 (3H, s), 3.90 (3H, s), 4.08 (1H, tt, J=11.94, 3.98 Hz), 7.51 (1H,dd, J=12.21, 1.23 Hz), 7.83 (1H, s), 8.09 (1H, s), 8.21 (1H, s), 8.37(1H, s), 8.96 (1H, s), 9.09 (1H, s); ESIMS found for C₂₁H₂₅FN₆O m/z397.2 (M+1).

1-Methyl-3-(6-(2-methyloxazol-5-yl)isoquinolin-3-yl)-1-(1-methylpiperidin-4-yl)urea231.

White solid (360.0 mg, 0.95 mmol, 71.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.50-1.56 (2H, m), 1.74 (2H, qd, J=12.12, 3.98 Hz), 1.97(2H, td, J=11.73, 2.06 Hz), 2.17 (3H, s), 2.53 (3H, s), 2.79-2.85 (2H,m), 2.88 (3H, s), 4.09 (1H, tt, J=12.01, 3.91 Hz), 7.74 (1H, dd, J=8.51,1.65 Hz), 7.76 (1H, s), 8.02 (1H, s), 8.06 (1H, d, J=8.78 Hz), 8.22 (1H,s), 8.86 (1H, s), 9.05 (1H, s); ESIMS found for C₂₁H₂₅N₅O₂ m/z 380.2(M+1).

Example 15

The screening assay for Wnt activity is described as follows. Reportercell lines can be generated by stably transducing cancer cell lines(e.g., colon cancer) or primary cells (e.g., IEC-6 intestinal cells)with a lentiviral construct that includes a Wnt-responsive promoterdriving expression of the firefly luciferase gene.

SW480 colon carcinoma cells were transduced with a lentiviral vectorexpressing luciferase with a human Sp5 promoter consisting of a sequenceof eight TCF/LEF binding sites. SW480 cells stably expressing theSp5-Luc reporter gene and a hygromycin resistance gene were selected bytreatment with 150 μg/mL of hygromycin for 7 days. These stablytransduced SW480 cells were expanded in cell culture and used for allfurther screening activities. Each compound was dissolved in DMSO as a10 mM stock and used to prepare compound source plates. Serial dilution(1:3, 10-point dose-response curves starting from 10 μM) and compoundtransfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.)into 384-well white solid bottom assay plates (Greiner Bio-One) withappropriate DMSO backfill for a final DMSO concentration of 0.1%. ForSp5-Luc reporter gene assays, the cells were plated at 4,000 cells/wellin 384-well plates with a DMEM medium containing 1% fetal bovine serum,and 1% Penicillin-Streptomycin and incubated for 36 to 48 hours at 37°C. and 5% CO₂. Following incubation, 15 μl of BriteLite Plusluminescence reagent (Perkin Elmer) was added to each well of the384-well assay plates. The plates were placed on an orbital shaker for 2min and then luminescence was quantified using the Envision (PerkinElmer) plate reader. Readings were normalized to DMSO only treatedcells, and normalized activities were utilized for EC₅₀ calculationsusing the dose-response log (inhibitor) vs. response -variable slope(four parameters) nonlinear regression feature available in GraphPadPrism 5.0 (or Dotmatics). For EC₅₀ of >10 μM, the percent inhibition at10 μM is provided.

Table 2 shows the measured activity for representative compounds ofFormula I as described herein.

TABLE 2 Compound EC₅₀ (μM) 1 0.239 2 0.799 3 1.858 4 0.730 5 0.917 60.820 7 >10 (32.9%) 8 0.028 9 0.036 10 0.923 11 2.812 12 0.943 13 3.70314 5.351 15 >10 (40.1%) 16 1.460 17 4.099 18 0.671 19 >10 (22.4%) 202.644 21 0.657 22 0.434 23 0.725 24 1.186 25 >10 (34.3%) 26 6.948 270.927 28 1.108 29 >10 (45.6%) 30 3.309 31 2.058 32 >10 (30.5%) 33 3.49834 3.360 35 3.345 36 3.735 37 4.045 38 0.743 39 >10 (36.3%) 40 >10(29.6%) 41 >10 (29.7%) 42 >10 (25.5%) 43 0.239 44 0.799 45 1.858 460.730 47 0.917 48 0.820 49 >10 (32.9%) 50 0.028 51 0.036 52 0.923 532.812 54 0.943 55 3.703 56 5.351 57 >10 (40.1%) 58 1.460 59 4.099 600.671 61 >10 (22.4%) 62 2.644 63 0.657 64 0.434 65 0.725 66 1.186 67 >10(34.3%) 68 6.948 69 0.927 70 1.108 71 >10 (45.6%) 72 3.309 73 2.05874 >10 (30.5%) 75 3.498 76 3.360 77 3.345 78 3.735 79 4.045 80 0.74381 >10 (36.3%) 82 >10 (29.6%) 83 >10 (29.7%) 84 >10 (25.5%) 85 0.233 860.350 87 0.214 88 0.179 89 0.155 90 0.159 91 0.197 92 3.135 93 0.067 940.088 95 1.074 96 >10 (0%) 97 1.469 99 0.589 100 0.720 101 >10 (6.3%)102 3.254 103 2.971 104 3.603 105 >10 (15.8%) 106 3.432 108 >10 (19.9%)109 7.809 >10 110 (24.5%) 121 8.130 124 3.475 125 1.242 126 1.180 1283.181 129 1.806 130 4.036 131 3.918 134 0.593 135 5.686 136 2.107137 >10 (38.5%) 139 2.815 141 2.783 143 2.935 144 >10 (35.8%) 145 1.815146 3.109 147 3.327 148 3.440 149 1.397 150 2.192 151 >10 (4.4%) 153 >10(3.4%) 154 2.761 155 2.667 156 2.841 157 1.731 158 0.514 159 4.196 1600.309 161 0.736 162 0.588 163 0.604 164 0.638 165 0.498 166 0.525 1672.354 168 >10 (42.2%) 169 2.543 170 >10 (23.1%) 176 1.035 179 2.782 1888.209 193 >10 (8.4%) 194 0.681 195 >10 (13.8%) 196 3.975 197 1.419 1990.982 200 0.841 224 >10 (43.8%) 225 3.849 226 >10 (31.6%) 227 3.653228 >10 (46.3%) 229 >10 (0%) 230 >10 (0%) 231 3.892

Example 16

Representative compounds were screened using the assay procedure forDYRK1A kinase activity as described below.

Each compound was dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:3, 11-point dose-responsecurves from 10 M to 0.00016 M) and compound transfer was performed usingthe ECHO 550 (Labcyte, Sunnyvale, Calif.) into 1536-well black-walledround bottom plates (Corning).

The DYRK1A kinase assay was run using the Ser/Thr 18 peptide Z-lyteassay kit according to manufacturer's instructions (Life Technologies—aDivision of Thermo-Fisher). This is a non-radioactive assay usingfluorescence resonance energy transfer (FRET) between coumarin andfluorescein to detect kinase activity which is represented as a ratio ofcoumarin emission/fluorescein emission.

Briefly, recombinant DYRK1A kinase, ATP and Ser/Thr peptide 18 wereprepared in 1× Kinase buffer to final concentrations of 0.19 μg/mL, 30μM, and 4 μM respectively. The mixture was allowed to incubate with therepresentative compounds for one hour at room temperature. All reactionswere performed in duplicate. Unphosphorylated (“0% Control”) andphosphorylated (“100% control”) forms of Ser/Thr 18 served as controlreactions. Additionally, an 11-point dose-response curve ofStaurosporine (1 uM top) was run to serve as a positive compoundcontrol.

After incubation, Development Reagent A was diluted in DevelopmentBuffer then added to the reaction and allowed to further incubate forone hour at room temperature. The plate was read at Ex 400 Em 455 todetect the coumarin signal and Ex 400 Em 520 to measure the signal(EnVision Multilabel Plate Reader, PerkinElmer).

The Emission ratio (Em) was calculated as a ratio of the coumarin (C)emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm).The percent phosphorylation was then calculated using the followingformula: [1−((Em ratio×F100%)−C100%)/((C0%−C100%)+(Emratio×(F100%−F0%)))]. Dose-response curves were generated and inhibitoryconcentration (IC₅₀) values were calculated using non-linear regressioncurve fit in the Dotmatics' Studies Software (Bishops Stortford, UK).

Table 3 shows the measured activity for representative compounds ofFormula I as described herein.

TABLE 3 Compound EC₅₀ (μM) 1 0.004 2 0.004 3 0.004 4 0.004 5 0.003 60.003 7 0.376 8 0.002 9 0.002 10 0.004 11 0.010 12 0.016 13 0.013 140.033 15 0.061 16 0.005 17 0.018 18 0.003 19 0.110 20 0.005 21 0.006 220.005 23 0.004 24 0.007 25 0.014 26 0.038 27 0.006 28 0.004 29 0.018 300.027 31 0.024 32 0.017 33 0.009 34 0.015 35 0.026 36 0.012 37 0.007 380.006 39 0.015 40 0.029 41 0.027 42 0.012 43 0.002 44 0.005 45 0.003 460.006 47 0.006 48 0.020 49 0.021 50 0.020 51 0.014 52 0.009 53 0.038 540.007 55 0.006 56 0.004 57 0.009 58 0.006 59 0.003 60 0.007 61 0.007 620.007 63 0.017 64 0.008 65 0.070 66 0.003 67 0.007 68 0.007 69 0.003 700.002 71 0.006 72 0.003 73 0.003 74 0.006 75 0.003 76 0.002 77 0.006 780.002 79 0.002 80 0.003 81 0.002 82 0.003 83 0.002 84 0.002 85 0.002 860.002 87 0.003 88 0.002 89 0.002 90 0.004 91 0.005 92 0.010 93 0.002 940.002 95 0.004 96 0.846 97 0.014 99 0.004 100 0.003 101 0.022 102 0.005103 0.005 104 0.008 105 0.034 106 0.017 108 0.010 109 0.010 110 0.017121 0.035 124 0.035 125 0.004 126 0.005 128 0.016 129 0.018 130 0.037131 0.013 134 0.006 135 0.041 136 0.006 137 0.018 139 0.022 141 0.009143 0.011 144 0.020 145 0.002 146 0.022 147 0.018 148 0.014 149 0.007150 0.013 151 0.009 153 0.028 154 0.005 155 0.008 156 0.007 157 0.019158 0.005 159 0.027 160 0.004 161 0.010 162 0.011 163 0.005 164 0.011165 0.006 166 0.009 167 0.007 168 0.004 169 0.003 170 0.015 176 0.023179 0.018 188 0.003 193 0.033 194 0.003 195 0.005 196 0.006 197 0.003199 0.004 200 0.006 224 0.001 225 0.002 226 0.004 227 0.024 228 0.012229 1.000 230 0.021 231 0.016

Example 17

Representative compounds were screened using the assay procedure forGSK30 kinase activity as described below.

Each compound is dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:3, 11-point dose-responsecurves from 10 M to 0.0003 μM) and compound transfer was performed usingthe ECHO 550 (Labcyte, Sunnyvale, Calif.) into 1536-well black-walledround bottom plates (Corning).

The GSK30 kinase assay is run using the Ser/Thr 09 peptide Z-lyte assaykit according to manufacturer's instructions (Life Technologies—aDivision of Thermo-Fisher). This is a non-radioactive assay usingfluorescence resonance energy transfer (FRET) between coumarin andfluorescein to detect kinase activity which is represented as ratio ofcoumarin emission/fluorescein emission.

Briefly, recombinant GSK3β kinase, ATP and Ser/Thr peptide 09 areprepared in 1× Kinase buffer to final concentrations of 0.04 μg/mL, 46μM, and 4 μM respectively. The mixture is allowed to incubate with therepresentative compounds for one hour at room temperature. All reactionswere performed in duplicate. Unphosphorylated (“0% Control”) andphosphorylated (“100% control”) forms of Ser/Thr 18 serve as controlreactions.

After incubation, diluted Development Buffer is added to the reactionand allowed to further incubate for one hour at room temperature. Theplate is read at Ex 400 Em 455 to detect the coumarin signal and Ex 400Em 520 to measure the signal (EnVision Multilabel Plate Reader,PerkinElmer).

The Emission ratio (Em) is calculated as a ratio of the coumarin (C)emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm).The percent phosphorylation is then calculated using the followingformula: [1−((Em ratio×F100%)−C100%)/((C0%−C100%)+(Emratio×(F100%−F0%)))].

Dose-response curves are generated and inhibitory concentration (IC₅₀)values are calculated using non-linear regression curve fit in theDotmatics' Studies Software (Bishops Stortford, UK).

Table 4 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 4 Compound EC₅₀ (μM) 1 0.107 2 0.246 3 0.131 4 0.022 5 0.115 60.051 7 1.899 8 6.579 9 7.707 10 0.018 11 0.010 12 0.189 13 1.246 140.048 15 0.059 16 0.122 17 0.188 18 0.068 19 1.162 20 0.041 21 0.035 220.022 23 0.017 24 0.030 25 0.313 26 0.524 27 0.011 28 0.008 29 0.337 300.099 31 0.117 32 0.210 33 0.023 34 0.046 35 0.084 36 0.079 37 0.138 380.009 39 0.096 40 0.120 41 0.203 42 4.674 43 0.066 44 0.065 45 0.076 460.023 47 0.065 48 0.054 49 0.006 50 0.218 51 0.349 52 0.156 53 0.366 540.006 55 0.088 56 0.009 57 0.016 58 0.007 59 0.015 60 0.073 61 9.210 620.068 63 0.473 64 0.530 65 2.836 66 0.053 67 1.866 68 0.066 69 0.070 700.073 71 0.014 72 >10 73 >10 74 >10 75 3.802 76 2.068 77 >10 78 7.673 794.458 80 2.584 81 1.051 82 1.508 83 0.874 84 1.046 85 0.847 86 1.744 871.454 88 1.006 89 0.533 90 0.388 91 0.454 92 0.066 93 0.238 94 0.276 950.038 96 5.423 97 0.020 99 0.008 100 0.011 101 1.027 102 0.434 103 0.030104 0.149 105 0.550 106 0.320 108 0.671 109 0.175 110 0.314 121 0.082124 0.217 125 0.005 126 0.024 128 0.025 129 0.090 130 0.142 131 0.006134 0.019 135 0.022 136 0.080 137 0.068 139 0.033 141 0.050 143 1.782144 0.021 145 0.080 146 0.062 147 0.037 148 0.257 149 0.128 150 0.023151 0.103 153 0.532 154 0.124 155 0.668 156 0.034 157 >10 158 2.596159 >10 160 3.034 161 5.669 162 5.061 163 4.266 164 4.582 165 3.735 1666.378 167 0.096 168 0.020 169 0.047 170 0.052 176 0.207 179 0.026 1880.154 193 0.330 194 0.012 195 1.254 196 0.194 197 0.087 199 0.017 2000.014 224 0.703 225 0.407 226 1.188 227 4.500 228 0.255 229 6.707 2303.640 231 2.825

Example 18

Representative compounds were screened using the assay procedure for tauphosphorylation activity described below.

SH-SY5Y cells (human neuroblastoma) were cultured in DMEM/F-12 mediumsupplemented with 15% FBS, Non-essential Amino Acid andPenicillin/Streptomycin. Two days before treatment, cells were seededonto 96 well plates at 5×10⁴ cells/well.

The above synthesized compounds were screened using the cell assayprocedure to assess decrease Tau phosphorylation at Ser396 (pSer396)described below.

DMSO-resuspended compounds were dispensed to 8 wells as a serialtitration from 10 μM to 4.6 nM final in medium and cells were exposedovernight (16-18 h) in a humidified incubator at 36.6c before harvest.Wells were visually checked for cell death or change in morphology andsupernatants were tested for cytotoxicity by measurement of lactatedehydrogenase release (LDH, CytoToxOne kit, Promega) if necessary. Ascontrols, commercially available DYRK1A inhibitors, Harmine and Indywhich were shown to have good DYRK1A inhibition in the kinase assay withno CDK1 activity (EC₅₀ 18 and 53 nM respectively, 6 μM for CDK1) butweak EC₅₀ in the Tau assay>10 M.

Cells were lysed with RIPA buffer complemented with phosphatase andprotease inhibitors then lysates were spun down at 12,000 g for 10 minto remove any cellular debris. Lysates are then either directly testedfor pSer396 by ELISA (Life Technology, Kit KHB7031) or loaded on NuPageBis-Tris gels for western blot analysis. Colorimetric detection of ELISAsignal is performed by Cytation3 plate reader (Biotek) and thechemiluminescence signal for HRP-linked antibodies used in westernblotting is detected using a Carestream Image Station. The same pSer396antibody is used for detection of pTau in both assays.

Blot densitometry for pSer396 and β-actin were analyzed using ImageJ(NIH) and pSer396 Tau ELISA signal was used to plot, draw the curvefitting, and determine each compounds EC₅₀ in Prism (GraphPad).

Table 5 shows the activity of representative compounds as providedherein.

TABLE 5 pSer396 Tau EC₅₀ Compound (μM) 1 0.368 2 0.559 3 0.458 4 0.069 50.511 6 0.103 8 >10 9 >10 10 0.119 11 0.190 12 0.436 13 4.700 14 0.38215 0.981 16 0.286 17 0.743 18 0.186 20 0.524 21 0.566 22 0.126 23 0.16124 0.127 25 0.430 26 0.167 27 0.104 28 0.089 29 3.400 30 0.453 31 0.38632 0.891 33 0.321 34 0.456 35 0.543 36 0.843 37 0.497 38 0.067 39 0.53840 0.688 41 0.869 42 >10 43 0.362 44 0.445 45 0.320 46 0.091 47 0.174 480.359 49 0.135 50 0.779 51 0.656 52 1.100 53 2.300 54 0.097 55 0.178 560.092 57 0.136 58 0.058 59 0.035 60 1.100 61 >10 62 1.200 63 3.100 642.900 65 >10 66 0.168 67 >10 68 0.948 69 0.516 70 0.307 71 0.250 722.600 73 >10 74 >10 75 >10 76 >10 77 >10 78 >10 79 >10 80 >10 81 2.82882 5.900 83 >10 84 1.400 85 1.400 86 3.041 87 0.896 88 0.016 89 0.594 900.171 91 0.068 92 0.769 93 0.259 94 0.244 95 0.076 96 >10 97 0.184 990.208 100 0.113 101 5.400 102 2.600 103 1.300 104 0.712 105 2.200 1060.323 108 >10 109 3.100 110 2.100 121 0.953 124 0.612 125 0.114 1260.197 128 0.491 129 0.656 130 1.500 131 0.337 134 0.093 135 0.365 1360.309 137 0.573 139 1.400 141 0.594 143 7.200 144 >10 145 0.503 1461.000 147 1.100 148 0.599 149 1.100 150 0.272 151 2.600 153 >10 1540.580 155 0.384 156 0.615 157 0.720 158 >10 159 >10 160 >10 161 >10162 >10 163 >10 164 >10 165 >10 166 >10 167 0.288 168 0.578 169 0.154170 9.911 176 4.000 179 1.300 188 4.800 193 >10 194 0.218 195 >10 1970.570 199 0.234 200 0.095 204 >10 225 >10 226 >10 227 4.500 228 6.400

Example 19

Representative compounds were screened using the cell-based assayprocedure for signal of Tau phosphorylation at Threonine 212 (pT212Tau)in a transiently double transfected (Dyrk1a- and MAPT-overexpressing)cell type as described below.

HEK293T cells (transfectable human embryonic kidney cells) were culturedin DMEM medium supplemented with 10% FBS and 1% penicillin/streptomycin.

HEK293T cells were transiently transfected to overexpress Dyrkla andmicrotubule-associated protein Tau (MAPT) genes. Specifically, Dyrklaand MAPT expression vectors were obtained from OriGene (10 μg of each,catalog numbers SC314641 and RC216166, respectively). A MaxiPrep foreach vector was ordered and received from GeneWiz, yielding 874.5 g(resuspended at 1.749 μg/L) of the Dyrkla expression vector, and 898 μg(resuspended at 1.796 μg/μL) of MAPT.

HEK293T cells were seeded at 1.0×10⁷ cells in 10 mL per T-75 flask.After overnight incubation, HEK293T cells in the T-75 flasks weretransfected by creating a master mix of 10 μg of each expression vectorper flask, with Lipofectamine™ 3000 Transfection Reagent (Invitrogen,L3000015) diluted in Opti-MEM medium according to the manufacturer'ssuggested protocol. One T-75 flask was designated as a no-vectornegative control for pT212Tau signal.

After 4˜6 hours of incubation in transfection reagents, transientlydouble transfected HEK293T cells were dissociated by treatment withtrypsin EDTA and seeded at 1.0×10⁵ cells in 100 μL per well in 96-wellplates. No-vector negative controls were seeded in separate 96-wellplates to avoid the risk of the negative control cells picking up theoverexpression during incubation. At the time of seeding,DMSO-resuspended Samumed compounds were dispensed to eight wells as aserial dilution from 10 μM to 4.6 nM final concentration in medium, orat 0.12 μM to 0.05 nM with particularly potent compounds. Cells wereexposed to the representative compounds overnight (16-18 hours) in a 37°C. incubator.

96-Well flat-bottom plates were coated with 100 μL per well anti-HT7capture antibody (ThermoFisher, MN1000) diluted 1:300 in 1×PBS at 4° C.overnight, with shaking at 500 rpm. After overnight capture antibodyincubation, coated plates were washed four times with 200 L per well of1×PBS-0.05% Tween-20, and blocked for 1 hour with 200 μL per well of1×PBS with 2% BSA. After 1 hour of blocking, plates were washed fourtimes with 200 μL per well of 1×PBS-0.05% Tween-20, prior to sampleloading.

Wells of compound-treated cells were visually checked for cell deathbefore being washed with 200 μL per well of 1×DPBS supplemented withphosphatase inhibitor diluted to IX. Cells were then lysed with 100 μL1×RIPA buffer supplemented with phosphatase and protease inhibitors(each diluted to a final 1×). Cells were shaken at 500 rpm, 4° C. for 20minutes prior to further lysis (via manual scraping) and transfer to96-well V-bottom collection plates (Corning, 3894). V-bottom plates werecentrifuged at 4000 rpm, 4° C., for 15 minutes, and 100 μL of lysatesupernatant from each well was directly tested for pT212Tau signal bysandwich ELISA.

Specifically, lysates were directly transferred to the coated andblocked ELISA plates for 2 hours before plates were washed four timeswith 200 μL per well of 1×PBS-0.05% Tween-20 and probed with 100 μL perwell of anti-pT212Tau antibody (ThermoFisher, 44-740G) diluted 1:200 in1×PBS for 2 hours. Plates were washed four times with 200 μL per well of1×PBS-0.05% Tween-20 and probed with 100 μL per well of anti-rabbit/HRPconjugate (Cell Signaling Technology, 7074S) diluted 1:600 in 1×PBS for1 hour. Plates were washed four times with 200 μL per well of1×PBS-0.05% Tween-20 before 100 μL per well of TMB substrate solution(ThermoFisher, N301) was added. When colour development was observed,100 μL per well of stop solution (ThermoFisher, N600) was added, andcolorimetric detection of pT212Tau signal was read at 450 nm with theCytation 3 Cell Imaging Multi-Mode Reader (BioTek). The signal was usedto plot, draw the curves fitting, and determine the EC₅₀ values inGraphPad Prism for tested representative compounds.

Table 6 shows the activity of representative compounds as providedherein.

TABLE 6 Thr212 EC₅₀ Compound (μM) 22 0.011 58 0.093 61 0.015 67 0.006106 0.137 108 0.022 153 0.528 155 0.026 195 0.046 196 0.019 227 0.691228 >10 230 0.056 231 0.110

Example 20

Representative compounds were screened using the assay procedure toassess the effect on cell viability as described below.

SW480 colon carcinoma cells were transduced with a lentiviral vectorexpressing luciferase with a human Sp5 promoter consisting of a sequenceof eight TCF/LEF binding sites. SW480 cells stably expressing theSp5-Luc reporter gene and a hygromycin resistance gene were selected bytreatment with 150 μg/mL of hygromycin for 7 days. These stablytransduced SW480 cells were expanded in cell culture and used for allfurther screening activities. Each compound was dissolved in DMSO as a10 mM stock and used to prepare compound source plates. Serial dilution(1:3, 8-point dose-response curves from 10 μM to 0.0045 μM) and compoundtransfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.)into 384-well white solid bottom assay plates (Greiner Bio-One) withappropriate DMSO backfill for a final DMSO concentration of 0.1%.

For the Cell Viability Assays, the cells were plated at 2,000 cells/wellin 384-well plates with a DMEM medium containing 1% fetal bovine serum,and 1% Penicillin-Streptomycin and incubated for four days hours at 37°C. and 5% CO₂. Eight replicates of DMSO-treated cells served as controlsand cells treated with compound were performed in duplicate.

After incubation, 10 μL of CellTiter-Glo (Promega) was added to eachwell allowed to incubate for approximately 12 minutes. This reagent“results in cell lysis and generation of a luminescent signalproportional to the amount of ATP present. The amount of ATP is directlyproportional to the number of cells present in culture, in agreementwith previous reports. The CellTiter-Glo® Assay generates a “glow-type”luminescent signal, produced by the luciferase reaction (Promega.com)”.

After incubation, the plates were read at Ex 560 nm Em 590 nm (Cytation3, BioTek). Dose-response curves were generated and EC₅₀ concentrationvalues were calculated using non-linear regression curve fit in theGraphPad Prism (San Diego, Calif.) or Dotmatics' Studies Software(Bishops Stortford, UK). For EC₅₀ of >10 μM, the percent inhibition at10 μM is provided.

Table 7 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 7 Compound EC₅₀ (μM) 1 0.839 2 4.450 3 6.670 4 0.907 5 0.738 61.239 7 >10 (42.5%) 8 0.099 9 0.106 10 0.719 11 >10 (46.3%) 12 0.713 133.507 14 5.554 15 >10 (38.0%) 16 0.808 17 6.914 18 0.587 19 >10 (44.8%)20 3.067 21 1.064 22 2.053 23 2.124 24 3.644 25 >10 (40.3%) 26 8.527 272.093 28 >10 (37.8%) 29 >10 (28.2%) 30 6.838 31 3.803 32 >10 (8.3%) 334.627 34 3.765 35 4.548 36 5.699 37 6.890 38 1.078 39 >10 (27.3%) 40 >10(27.0%) 41 >10 (10.7%) 42 >10 (26.5%) 43 4.980 44 2.804 45 0.659 461.042 47 0.751 48 3.892 49 2.896 50 >10 (43.0%) 51 3.938 52 3.973 534.508 54 3.212 55 1.297 56 6.502 57 4.114 58 0.547 59 0.140 60 4.06061 >10 (13.1%) 62 3.640 63 2.572 64 3.534 65 >10 (7.3%) 66 1.221 673.991 68 >10 (47.2%) 69 1.704 70 1.721 71 >10 (46.7%) 72 0.489 73 0.48174 0.479 75 0.443 76 0.462 77 0.496 78 0.468 79 0.464 80 1.597 81 0.48682 3.313 83 0.305 84 0.494 85 0.487 86 0.515 87 0.489 88 0.480 89 0.48090 0.312 91 0.314 92 4.084 93 0.098 94 0.104 95 0.766 96 >10 (2.3%) 970.806 99 1.081 100 1.531 101 >10 (18.8%) 102 3.029 103 6.085 104 4.589105 >10 (16.9%) 106 2.956 108 >10 (7.8%) 109 4.127 110 >10 (1.5%)121 >10 (36.5%) 124 1.019 125 1.657 126 0.488 128 4.371 129 3.624 1304.209 131 >10 (35.9%) 134 2.736 135 >10 (27.8%) 136 1.117 137 >10(39.0%) 139 7.354 141 1.569 143 3.362 144 3.769 145 1.494 146 3.835 1474.141 148 1.201 149 1.335 150 3.922 151 >10 (0%) 153 >10 (0%) 154 0.761155 0.807 156 2.552 157 2.382 158 0.781 159 7.997 160 0.415 161 0.660162 0.653 163 0.795 164 0.782 165 0.752 166 0.671 167 3.343 168 >10(19.4%) 169 1.127 170 >10 (27.0%) 176 >10 (8.3%) 179 5.059 188 >10(28.0%) 193 >10 (12.8%) 194 1.260 195 >10 (13.0%) 196 6.112 197 1.270199 1.645 200 1.388 224 >10 (24.6%) 225 >10 (28.7%) 226 >10 (46.9%)227 >10 ($1.9%) 228 >10 (178.4%) 229 >10 (49.5%) 230 >10 (31.9%) 231 >10(41.6%)

Example 21

Representative compounds were screened using primary human fibroblasts(derived from IPF patients) treated with TGF-β1 to determine theirability to inhibit the fibrotic process.

Human Fibroblast Cell Culture:

Primary human fibroblasts derived from IPF patients (LL29 cells)[¹Xiaoqiu Liu, et. al., “Fibrotic Lung Fibroblasts Show BluntedInhibition by cAMP Due to Deficient cAMP Response Element-BindingProtein Phosphorylation”, Journal of Pharmacology and ExperimentalTherapeutics (2005), 315(2), 678-687; ²Watts, K. L., et. al., “RhoAsignaling modulates cyclin D1 expression in human lung fibroblasts;implications for idiopathic pulmonary fibrosis”, Respiratory Research(2006), 7(1), 88] were obtained from American Type Culture Collection(ATCC) and expanded in F12 medium supplemented with 15% Fetal BovineSerum and 1% Penicillin/Streptomycin.

Compound Screening:

Each compound was dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:2, 11-point dose-responsecurves from 10 M to 0.94 nM) and compound transfer was performed usingthe ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well clear bottomassay plates (Greiner Bio-One) with appropriate DMSO backfill for afinal DMSO concentration of 0.1%. LL29 cells were plated at 1,500cells/well in 70 μL/well F12 medium supplemented with 1% Fetal BovineSerum. TGF-β1 (Peprotech; 20 ng/mL) was added to the plates to inducefibrosis (ref. 1 and 2 above). Wells treated with TGF-31 and containingDMSO were used as positive control, and cells with only DMSO werenegative control. Cells were incubated at 37° C. and 5% CO₂ for 4 days.Following incubation for 4 days, SYTOX green nucleic acid stain (LifeTechnologies [Thermo Fisher Scientific]) was added to the wells at afinal concentration of 1 μM and incubated at room temperature for 30min. Cells were then fixed using 4% formaldehyde (Electron MicroscopySciences), washed 3 times with PBS followed by blocking andpermeabilization using 3% Bovine Serum Albumin (BSA; Sigma) and 0.3%Triton X-100 (Sigma) in PBS. Cells were then stained with antibodyspecific to α-smooth muscle actin (αSMA; Abcam) (ref. 1 and 2 above) in3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) inPBS, and incubated overnight at 4° C. Cells were then washed 3 timeswith PBS, followed by incubation with Alexa Flor-647 conjugatedsecondary antibody (Life Technologies [Thermo Fisher Scientific]) andDAPI in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100(Sigma) in PBS at room temperature for 1 hour. Cells were then washed 3times with PBS and plates were sealed for imaging. αSMA staining wasimaged by excitation at 630 nm and emission at 665 nm and quantifiedusing the Compartmental Analysis program on the CellInsight CX5 (ThermoScientific). Dead or apoptotic cells were excluded from analysis basedon positive SYTOX green staining. % of total cells positive for αSMAwere counted in each well and normalized to the average of 11 wellstreated with TGF-β1 on the same plate using Dotmatics' Studies Software.The normalized averages (fold change over untreated) of 3 replicatewells for each compound concentration were used to create dose-responsescurves and EC₅₀ values were calculated using non-linear regression curvefit in the Dotmatics' Studies Software. For EC₅₀ of >10 μM, the percentinhibition at 10 μM is provided.

Table 8 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 8 Compound EC₅₀ (μM) 1 0.445 2 0.150 3 0.153 4 0.229 5 0.113 60.132 7 2.664 8 0.095 9 0.157 10 0.208 11 >10 (3.8%) 12 0.102 13 >10(38.2%) 14 1.379 15 0.896 16 0.172 17 1.433 18 0.149 19 >10 (20.6%) 200.480 21 0.340 22 0.602 23 0.489 24 0.573 25 3.866 26 >10 (48.4%) 270.235 28 0.448 29 >10 (3.2%) 30 4.112 31 3.709 32 0.771 33 >10 (49.9%)34 >10 (48.5%) 35 1.022 36 5.202 37 0.244 38 0.112 39 2.589 40 3.713 411.220 42 >10 (6.4%) 43 0.230 44 0.247 45 0.095 46 0.640 47 0.262 480.718 49 0.643 50 1.472 51 2.492 52 1.729 53 1.579 54 0.412 55 0.678 560.285 57 1.168 58 0.788 59 0.297 60 4.858 61 2.770 62 1.229 63 1.281 640.683 65 2.348 66 0.160 67 >10 (5.2%) 68 1.525 69 0.210 70 0.124 714.658 72 0.937 73 1.706 74 1.253 75 0.450 76 0.611 77 2.149 78 0.526 790.572 80 2.714 81 0.309 82 >10 (31.2%) 83 0.483 84 0.630 85 0.557 860.556 87 0.132 88 0.311 89 0.190 90 0.299 91 0.289 92 2.706 93 0.145 940.125 95 0.276 96 >10 (36.0%) 97 0.200 99 0.072 100 0.064 101 3.074 1022.400 103 0.392 104 0.220 105 0.812 106 0.707 108 >10 (18.2%) 109 >10(19.5%) 110 1.968 121 >10 (10.4%) 124 0.451 125 0.442 126 0.286 1286.627 129 1.992 130 3.298 131 1.930 134 0.579 135 2.140 136 0.418 1373.134 139 2.351 141 0.321 143 >10 (40.4%) 144 1.379 145 0.072 146 >10(35.1%) 147 1.644 148 0.286 149 0.216 150 >10 (43.7%) 151 2.687 153 >10(9.0%) 154 0.240 155 1.065 156 2.382 157 5.794 158 1.216 159 >10 (31.4%)160 1.010 161 3.004 162 2.004 163 0.876 164 1.479 165 0.998 166 1.880167 0.293 168 1.295 169 0.148 170 7.091 176 >10 (8.4%) 179 >10 (10.1%)188 2.476 193 >10 (6.5%) 194 0.328 195 >10 (23.4%) 196 0.184 197 0.233199 3.199 200 0.533 224 >10 (13.1%) 225 >10 (24.8%) 226 >10 (33.2%) 2289.985 229 9.985 230 6.326 231 2.952

Example 22

Representative compounds were screened using the cell-based assayprocedure for secreted cytokines in a Lipopolysaccharide-stimulatedmouse glial cell line described below.

BV-2 cells (mouse microglial cells) were cultured in 1:1 DMEM mediumsupplemented with 10% FBS, and 1% penicillin/streptomycin.

BV-2 cells are plated at 35,000 cells/well in a volume of 100 μl for atleast 4 hours before compounds are added. DMSO-resuspended compoundswere first dispensed in a 96-well plate and serial diluted from 10 μM to4.6 nM final concentration in medium. Compounds were added to cellsovernight. 250 ng/mL of lipopolysaccharide (Escherichia coli O11:B4,SIGMA) was added for 5 hours. Supernatant is removed and saved forfurther cytokine detection. The original plates with seeded cells weretested for cytotoxicity by measure of adenosine triphosphate (ATP)release by adding CellTiter-Glo® diluted 1:4 in distilled water (G7573,Promega) and transferring lysed cells to a completely black 96-wellplate to be read with the Cytation3. Supernatant was then diluted 1:2with a diluent from V-PLEX cytokine Kit and directly tested for thesecreted cytokines TNFα, IL-6 and KC-GRO using electrochemiluminescence(Meso Scale Discovery). The standard curve for each cytokine was used toconvert the electrochemiluminescent signal into pg of protein per mL.The signal was used to plot, draw the curve fitting, and determine eachcompounds EC₅₀ in Prism (GraphPad).

Table 9 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 9 Compound EC₅₀ (μM) 1 0.067 2 0.001 3 0.033 4 0.218 5 0.042 60.011 9 0.076 10 1.050 11 0.051 12 0.006 13 0.252 14 0.456 15 0.193 160.022 17 0.242 18 0.001 20 0.053 21 1.100 22 0.697 23 0.023 24 0.054 250.150 26 9.400 27 0.040 28 0.017 29 0.220 30 0.155 31 0.271 32 0.136 330.032 34 0.589 35 0.355 36 0.063 37 0.014 38 0.043 39 0.160 40 0.919 410.682 42 0.042 43 0.022 44 0.034 45 0.029 46 0.064 47 0.034 48 0.181 500.600 51 0.070 52 0.206 53 0.426 54 0.120 55 0.012 56 0.110 57 0.108 580.256 59 0.009 60 1.360 61 0.043 62 0.054 63 0.196 64 0.449 65 1.080 660.027 67 0.095 68 0.585 69 0.016 70 0.012 71 0.107 72 0.624 73 0.630 740.214 75 0.046 76 0.028 77 0.108 78 0.037 79 0.063 80 6.100 81 0.035 820.100 83 0.049 84 0.502 85 0.494 86 0.374 87 0.379 88 0.107 89 0.391 900.089 91 0.103 92 0.642 93 0.391 95 0.132 96 3.490 97 0.047 99 0.239 1000.017 101 0.328 102 0.123 103 0.117 104 0.076 105 0.236 106 0.115 1080.076 109 0.053 110 0.239 121 0.409 124 0.096 125 0.464 126 0.158 1280.220 129 0.364 130 1.370 131 0.440 134 0.496 135 1.400 136 0.032 1370.442 139 0.271 141 0.026 143 0.227 144 2.980 145 0.0420 146 0.189 1470.248 148 0.047 149 0.055 150 0.097 151 0.250 153 2.060 155 0.139 1560.369 157 0.854 158 0.776 159 0.118 161 1.500 163 0.122 164 0.145 1650.181 166 0.119 167 0.033 168 0.066 169 0.108 170 3.100 176 0.3260 1790.390 188 0.136 193 1.420 194 0.066 195 0.065 196 0.723 197 0.054 1990.169 200 0.202 225 >10 226 >10 227 0.875 228 0.556 230 0.520 231 0.396

Example 23

Representative compounds were screened using the following assayprocedure to determine their ability to inhibit IL-6 and thereforedemonstrate their anti-inflammatory properties.

Human Peripheral Blood Mononuclear Cells:

Fresh Normal PB MNC (Catalog # PB001, AllCells, Alameda, Calif.) wereshipped overnight at 4° C. and resuspended in Roswell Park MemorialInstitute (RPMI) 1640 Medium, with GlutaMAX Supplement (Catalog#61870127, ThermoFisher Scientific, Waltham, Mass.) supplemented with 1%Penicillin-Streptomycin (Catalog #151401633 ThermoFisher Scientific,Waltham, Mass.) and 1% fetal bovine serum (FBS) (Catalog #16140089,ThermoFisher Scientific, Waltham, Mass.) assay media.

Compound Screening:

Fresh normal human peripheral blood mononuclear cells (huPBMCs) wereresuspended in 1% FBS-RPMI assay media with 1% Penicillin-Streptomycin1% to a cell concentration of 1×10e6 cells/mL. Each compound wasdissolved in DMSO (Catalog # D8418-100 ml, Sigma-Aldrich, St. Louis,Mo.) as a 10 mM stock and used to prepare compound source plates. Serialdilution (1:3, 10-point dose-response curves starting from 10 μM) andcompound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale,Calif.) into 384-well white Proxiplate-Plus assay plates (Catalog#6008289, PerkinElmer, Shelton, Conn.) with appropriate DMSO backfillfor a final DMSO concentration of 0.25%. huPBMCs were plated at 5000cells/well in the 384-well Proxiplate-Plus assay plates and incubated at37° C.-5% CO₂ for 2 hours. 50 ng/mL of Lipopolysaccharides fromEscherichia coli 0111:B4 (Catalog # L5293-2 ML, Sigma-Aldrich, St.Louis, Mo.) was added after 2 hours and cells were incubated for another22 hours at 37° C.-5% CO₂. After 22 hour incubation, a mixture ofanti-IL6 XL665 and anti-IL-6 Cryptate diluted in reconstitution buffer(Catalog #62IL6PEC, Cisbio Inc., Bedford, Mass.) was added to each well.Following incubation for 3 hours at room temperature, HomogeneousTime-Resolved Fluorescence (HTRF) was measured using the Envision(Perkin Elmer, Shelton, Conn.) at 665 nm and 620 nM. The ratio offluorescence at 665 nm to 620 nm was used as a readout for IL-6quantification. All samples were processed in duplicate. Readings werenormalized to DMSO treated cells and normalized activities were utilizedfor EC₅₀ calculations. EC₅₀ was determined using software generated byDotmatics Limited (Windhill Bishops Stortford Herts, UK) using theLevenberg-Marquardt 4 parameter fitting procedure with finite differentgradients. For EC₅₀ of >10 μM, the percent inhibition at 10 μM isprovided.

Table 10 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 10 Compound EC₅₀ (μM) 1 3.040 2 1.284 3 1.123 4 0.489 5 1.050 60.967 7 9.417 8 0.932 9 1.874 10 9.219 11 >10 (38.4%) 12 1.122 13 >10(17.6%) 14 >10 (12.5%) 15 >10 (15.8%) 16 1.035 17 3.436 18 1.250 193.217 20 >10 (13.4%) 21 9.368 22 6.658 23 9.372 24 8.808 25 >10 (8.0%)26 >10 (5.6%) 27 >10 (2.8%) 28 >10 (4.3%) 29 >10 (6.0%) 30 >10 (9.3%)31 >10 (19.8%) 32 >10 (10.1%) 33 9.321 34 >10 (7.0%) 35 >10 (9.6%)36 >10 (4.0%) 37 1.342 38 >10 (3.2%) 39 9.395 40 9.699 41 >10 (9.4%)42 >10 (6.4%) 43 1.069 44 1.130 45 0.655 46 3.764 47 0.945 48 9.07449 >10 (9.0%) 50 9.204 51 3.239 52 3.698 53 9.359 54 9.626 55 >10(18.3%) 56 3.369 57 >10 (6.1%) 58 9.569 59 0.129 60 >10 (5.7%) 61 >10(5.2%) 62 >10 (8.5%) 63 4.797 64 4.630 65 >10 (4.8%) 66 0.997 67 >10(29.6%) 68 4.058 69 1.019 70 0.952 71 9.371 72 1.580 73 2.068 74 1.12675 0.857 76 0.927 77 1.936 78 1.052 79 1.345 80 7.642 81 1.120 82 >10(47.6%) 83 1.126 84 1.301 85 1.224 86 2.170 87 1.174 88 1.196 89 1.05190 0.606 91 0.679 92 3.178 93 0.280 94 0.319 95 0.339 96 >10 (3.6%) 970.365 99 1.362 100 2.016 101 3.589 102 2.917 103 1.080 104 1.135 1051.570 106 1.114 108 >10 (4.1%) 109 >10 (6.9%) 110 >10 (7.0%) 121 >10(5.4%) 124 1.882 125 9.270 126 0.363 128 >10 (8.0%) 129 >10 (4.5%)130 >10 (12.2%) 131 1.930 134 7.132 135 >10 (0%) 136 0.463 137 2.278139 >10 (@6.6%) 141 0.388 143 >10 (5.7%) 144 >10 (14.3%) 145 0.371146 >10 (2.1%) 147 >10 (36.8%) 148 0.414 149 0.379 150 >10 (5.7%)151 >10 (13.1%) 153 >10 (9.0%) 154 1.132 155 1.065 156 >10 (28.8%)157 >10 (0%) 158 3.355 159 >10 (1.6%) 160 3.297 161 >10 (42.2%) 162 >10(44.7%) 163 5.716 164 3.386 165 2.846 166 3.550 167 1.245 168 >10(14.2%) 169 1.017 170 >10 (4.4%) 176 >10 (8.4%) 179 >10 (10.1%) 1885.769 193 >10 (6.5%) 194 3.087 195 >10 (23.4%) 196 1.211 197 0.994 1993.856 200 3.982 224 >10 (13.7%) 225 >10 (6.9%) 226 >10 (4.5%) 227 >10(4.9%) 228 >10 (3.3%) 229 8.955 230 >10 (36.6%) 231 8.278

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, of Formula I:

wherein: R¹, R², R⁴, and R⁵ are independently selected from the groupconsisting of H and halide; R³ is a 5-membered heteroaryl substitutedwith 1-4 R²⁶; with the proviso that R³ is not

R⁶ is selected from the group consisting of —CH₂phenyl substituted with1-5 R⁴¹, —CH═CHphenyl optionally substituted with halide, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R²⁷,-carbocyclyl substituted with 1-5 R²⁸, and

wherein —(C₁₋₄ alkylene) is, optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₃ alkyl); wherein n is 1-4, mis 0-2 and each Z is independently selected from the group consisting ofCR³² and N; each R²⁶ is independently unsubstituted —(C₁₋₅ alkyl); eachR²⁷ is independently selected from the group consisting of halide and—N(R⁴³)(R⁴⁴), with the proviso that if one or more R²⁷ is halide, atleast one R²⁷ is —N(R⁴³)(R⁴⁴); each R²⁸ is independently —N(R³³)(R³⁴);each R³² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl); R³³is attached to the nitrogen and selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl); R³⁴is attached to the nitrogen and is selected from the group consisting ofunsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R³⁹, —(C₁₋₄ alkylene)OR³⁵; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore halides or one or more unsubstituted —(C₁₋₃ alkyl); each R³⁵ isindependently selected from the group consisting of H and unsubstituted—(C₁₋₅ alkyl); each R³⁸ is independently selected from the groupconsisting of halide and unsubstituted —(C₁₋₅ alkyl); each R³⁹ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁰;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more halides or one or more unsubstituted —(C₁₋₃ alkyl);each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴¹ is halide; each R⁴³ is attached to the nitrogen and selectedfrom the group consisting of H, unsubstituted —(C₁₋₅ alkyl),unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl), andunsubstituted —(C₁₋₅ haloalkyl); each R⁴⁴ is attached to the nitrogenand is selected from the group consisting of H, unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R³⁹, and —(C₁₋₄ alkylene)OR³⁵; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more halides or one or more unsubstituted —(C₁₋₃ alkyl); each p isindependently 0 or 1; and wherein one or more H are optionally replacedby D.
 2. A compound, or a pharmaceutically acceptable salt thereof, ofFormula I:

wherein: R¹, R², R⁴, and R⁵ are independently selected from the groupconsisting of H and halide; R³ is selected from the group consisting of:

wherein each of R⁷-R²⁵ is, independently, a substituent or a single bondconnecting R³ to the isoquinoline ring; wherein only one of R⁷-R¹⁰ (whenpresent) is a bond, only one of R¹¹-R¹⁴ (when present) is a bond, onlyone of R¹⁵-R¹⁷ (when present) is a bond, only one of R¹⁸-R²⁰ (whenpresent) is a bond, only one of R²¹-R²³ (when present) is a bond, andonly one of R²⁴-R²⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,or R¹⁸ can serve as the point of attachment of R³ to the isoquinolinering; likewise, any one of the carbon atoms attached to R⁸, R⁹, R¹⁰,R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, and R²⁵ can serveas the point of attachment of R³ to the isoquinoline ring; so that: whenthe nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring; when the carbon atom to which R⁸is attached serves as the point of attachment of R³ to the isoquinolinering, then R⁸ is a single bond connecting R³ to the isoquinoline ring;when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring; when the carbon atom to whichR¹⁰ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁰ is a single bond connecting R³ to theisoquinoline ring; when the nitrogen atom to which R¹¹ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹¹ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹² is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹² is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R¹³ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹³ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹⁴ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹⁴ is a single bond connecting R³to the isoquinoline ring; when the nitrogen atom to which R¹⁵ isattached serves as the point of attachment of R³ to the isoquinolinering, then R¹⁵ is a single bond connecting R³ to the isoquinoline ring;when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring; when the carbon atom to whichR¹⁷ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁷ is a single bond connecting R³ to theisoquinoline ring; when the nitrogen atom to which R¹⁸ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹⁸ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹⁹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹⁹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁶ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁰ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²¹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²¹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²² is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²² is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²³ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²³ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁴ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁴ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²⁵ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²⁵ is a single bond connecting R³to the isoquinoline ring; R⁶ is selected from the group consisting of—CH₂phenyl substituted with 1-5 R⁴¹, —CH═CHphenyl optionally substitutedwith halide, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-5 R²⁷, -carbocyclyl substituted with 1-5 R²⁸, and

wherein —(C₁₋₄ alkylene) is, optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₃ alkyl); wherein n is 1-4, mis 0-2 and each Z is independently selected from the group consisting ofCR³² and N; R⁷ is selected from the group consisting of a single bondand unsubstituted —(C₁₋₅ alkyl); R⁸, R⁹, and R¹⁰ are independentlyselected from the group consisting of a single bond, H, andunsubstituted —(C₁₋₅ alkyl); R¹¹ is selected from the group consistingof a single bond, H, and unsubstituted —(C₁₋₅ alkyl); R¹², R¹³, and R¹⁴are independently selected from the group consisting of a single bond,H, and unsubstituted —(C₁₋₅ alkyl); R¹⁵ is selected from the groupconsisting of a single bond, H, and unsubstituted —(C₁₋₅ alkyl); R¹⁶ andR¹⁷ are independently selected from the group consisting of a singlebond, H, and unsubstituted —(C₁₋₅ alkyl); R¹⁸ is selected from the groupconsisting of a single bond, H, and unsubstituted —(C₁₋₅ alkyl); R¹⁹ andR²⁰ are independently selected from the group consisting of a singlebond, H, and unsubstituted —(C₁₋₅ alkyl); R²¹, R²², and R²³ areindependently selected from the group consisting of a single bond, H,and unsubstituted —(C₁₋₅ alkyl); R²⁴ and R²⁵ are independently selectedfrom the group consisting of a single bond, H, and unsubstituted —(C₁₋₅alkyl); each R²⁷ is independently selected from the group consisting ofhalide, and —N(R⁴³)(R⁴⁴), with the proviso that if one or more R²⁷ ishalide, at least one R²⁷ is —N(R⁴³)(R⁴⁴); each R²⁸ is independently—N(R³³)(R³⁴); each R³² is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl); R³³ is attached to the nitrogen and selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl); R³⁴ is attached to the nitrogen and is selected from thegroup consisting of unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, —(C₁₋₄alkylene)_(p)carbocyclyl optionally substituted with 1-12 R³⁹, —(C₁₋₄alkylene)OR³⁵; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more halides or unsubstituted —(C₁₋₃alkyl); each R³⁵ is independently selected from the group consisting ofH and unsubstituted —(C₁₋₅ alkyl); each R³⁸ is independently selectedfrom the group consisting of halide and unsubstituted —(C₁₋₅ alkyl);each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁰;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more halides or one or more unsubstituted —(C₁₋₃ alkyl);each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴¹ is halide; each R⁴³ is attached to the nitrogen and selectedfrom the group consisting of H, unsubstituted -(C₁₋₅ alkyl),unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl), andunsubstituted —(C₁₋₅ haloalkyl); each R⁴⁴ is attached to the nitrogenand is selected from the group consisting of H, unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅ alkynyl),unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, —(C₁₋₄ alkylene)_(p)carbocyclyloptionally substituted with 1-12 R³⁹, and —(C₁₋₄ alkylene)OR³⁵; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more halides or one or more unsubstituted —(C₁₋₃ alkyl); each X is 0or S; each p is independently 0 or 1; and wherein one or more H areoptionally replaced by D.
 3. The compound of claim 1, wherein thecompound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 4. A compound, or apharmaceutically acceptable salt thereof, of Formula I:

wherein: R¹, R², R⁴, and R⁵ are independently selected from the groupconsisting of H and halide; R³ is a 5-membered heteroaryl substitutedwith 1-4 R²⁶; with the proviso that R³ is not

R⁶ is selected from the group consisting of —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R²⁷,-carbocyclyl optionally substituted with 1-5 R²⁸, and —N(R³⁰)(R³¹);wherein —(C₁₋₄ alkylene) is, optionally substituted with one or morehalides or one or more unsubstituted —(C₁₋₃ alkyl); each R²⁶ isindependently unsubstituted —(C₁₋₅ alkyl); each R²⁷ is independentlyselected from the group consisting of halide, unsubstituted —(C₁₋₅alkyl), unsubstituted —(C₁₋₉ haloalkyl), —OR³⁵, and —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-5 R³⁶; wherein—(C₁₋₄ alkylene) is, optionally substituted with one or more halides orone or more unsubstituted —(C₁₋₃ alkyl); each R²⁸ is independentlyselected from the group consisting of —N(R³³)₂, —(C₁₋₄ alkylene)OR³⁵,—C(═O)(R³⁷), and —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-5 R³⁶; wherein each —(C₁₋₄ alkylene) is independently, optionallysubstituted with one or more halides or one or more unsubstituted —(C₁₋₃alkyl); R³⁰ is attached to the nitrogen and is selected from the groupconsisting of H and unsubstituted —(C₁₋₅ alkyl); R³¹ is attached to thenitrogen and is heterocyclyl optionally substituted with 1-5 R³⁸; R³³ isattached to the nitrogen and selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl), andunsubstituted —(C₂₋₅ alkynyl); each R³⁵ is independently selected fromthe group consisting of H and unsubstituted —(C₁₋₅ alkyl); each R³⁶ isselected from the group consisting of unsubstituted —(C₁₋₅ alkyl) andunsubstituted —(C₁₋₅ haloalkyl); R³⁷ is -heterocyclyl optionallysubstituted with one or more halides or one or more unsubstituted —(C₁₋₅alkyl); each R³⁸ is independently selected from the group consisting ofhalide and unsubstituted —(C₁₋₅ alkyl); each p is independently 0 or 1;and wherein one or more H are optionally replaced by D.
 5. The compoundof claim 4, wherein the compound of Formula I is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 6. A compound, or apharmaceutically acceptable salt thereof, of Formula I:

wherein: R¹, R², R⁴, and R⁵ are independently selected from the groupconsisting of H and halide; R³ is a 5-membered heteroaryl optionallysubstituted with 1-4 R²⁶; R⁶ is a selected from the group consisting of-phenyl substituted with 1-5 R⁴² and 6-membered heteroaryl optionallysubstituted with 1-6 R²⁹; each R²⁶ is independently unsubstituted —(C₁₋₅alkyl); each R²⁹ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl) and heterocyclyl optionally substituted with1-5 R³⁶; each R³⁶ is independently unsubstituted (C₁₋₅ alkyl); each R⁴²is independently selected from the group consisting of halide, —OMe, andunsubstituted —(C₁₋₅ alkyl); and wherein one or more H are optionallyreplaced by D.
 7. The compound of claim 6, wherein the compound ofFormula I is selected from the group consisting of:

and or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 9. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 2,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 10. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 4, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 11. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 6, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 12. The compound of claim 2, wherein R³ isselected from the group consisting of:

and X is O or S.
 13. The compound of claim 12, wherein R³ is selectedfrom the group consisting of:

wherein R⁷ is —(C₁₋₂ alkyl), and R¹¹, R¹⁴, R²³, and R²⁴ areindependently selected from the group consisting of H and —(C₁₋₂ alkyl).14. The compound of claim 13, wherein R⁶ is a -heterocyclyl optionallysubstituted with 1-2 R²⁷.
 15. The compound of claim 13, wherein R⁶ is a—CH₂heterocyclyl optionally substituted with 1-2 R²⁷.
 16. The compoundof claim 14, wherein R⁶ is either a piperidinyl or a pyrrolidinyl bothoptionally substituted with 1-2 R²⁷.
 17. The compound of claim 13,wherein R⁶ is selected from the group consisting of

and q is
 1. 18. The compound of claim 16, wherein R⁶ is a piperidinylsubstituted with one —N(R⁴³)(R⁴⁴).
 19. The compound of claim 17, whereinR⁴³ is H or Me and R⁴⁴ is —C₁₋₄ haloalkyl.
 20. The compound of claim 13,wherein R⁶ is —carbocyclyl substituted with 1-2 R²⁸.
 21. The compound ofclaim 4, wherein R³ is selected from the group consisting of a pyrazolylsubstituted with one —(C₁₂ alkyl), imidazolyl substituted with 1-2 —(C₁₂alkyl), oxazolyl substituted with one —(C₁₋₂ alkyl), and thiadiazolylsubstituted with one —(C₁₋₂ alkyl).
 22. The compound of claim 21,wherein R⁶ is -heterocyclyl optionally substituted with 1-2 R²⁷.
 23. Thecompound of claim 22, wherein R⁶ is selected from the group consistingof

and q is
 1. 24. A method of inhibiting one or more proteins in the Wntpathway, the method comprising contacting a cell with an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable salt,or a pharmaceutical composition.
 25. A method of inhibiting one or moreproteins in the Wnt pathway, the method comprising contacting a cellwith an effective amount of a compound of claim 2, or a pharmaceuticallyacceptable salt, or a pharmaceutical composition.
 26. A method ofinhibiting one or more proteins in the Wnt pathway, the methodcomprising contacting a cell with an effective amount of a compound ofclaim 4, or a pharmaceutically acceptable salt, or a pharmaceuticalcomposition.
 27. A method of inhibiting one or more proteins in the Wntpathway, the method comprising contacting a cell with an effectiveamount of a compound of claim 6, or a pharmaceutically acceptable salt,or a pharmaceutical composition.
 28. The method of claim 24, wherein thecell is a human cancerous cell.
 29. The method of claim 25, wherein thecell is a human cancerous cell.
 30. The method of claim 26, wherein thecell is a human cancerous cell.
 31. The method of claim 27, wherein thecell is a human cancerous cell.
 32. The method of claim 24, wherein theprotein is a kinase and the kinase is selected from the group consistingof DYRK or GSK families of kinases.
 33. The method of claim 25, whereinthe protein is a kinase and the kinase is selected from the groupconsisting of DYRK or GSK families of kinases.
 34. The method of claim26, wherein the protein is a kinase and the kinase is selected from thegroup consisting of DYRK or GSK families of kinases.
 35. The method ofclaim 27, wherein the protein is a kinase and the kinase is selectedfrom the group consisting of DYRK or GSK families of kinases.